Method

ABSTRACT

There is provided a method of producing a mixed metal compound comprising at least Mg 2+  and at least Fe +  having an aluminium content of less than 10000 ppm, having an average crystal size of less than 20 nm (200 A) comprising the steps of: (a) combining a Mg 2+  salt and a Fe 3+  salt with Na 2 CO 3  and NaOH to produce a slurry, wherein the pH of the slurry is maintained at from 9 5 to 1 1, and wherein the Na 2 CO 3  is provided at an excess of 0 to 4.0 moles than is required to complete the reaction (b) subjecting the slurry to mixing under conditions providing a power per unit volume of 0 03 to 1.6 kW/m 3  (c) separating the mixed metal compound from the slurry, to obtain a crude product having a dry solid content of at least 10 wt % (d) drying the crude product either by (i) heating the crude product to a temperature of no greater than 150° C. and sufficient to provide a water evaporation rate of 0.05 to 1 5 kg water per hour per kg of dry product, or (H) exposing the crude product to rapid drying at a water evaporation rate of 500 to 50000 kg water per hour per kg of dry product.

FIELD OF THE INVENTION

The present invention relates to a method for producing mixed metalcompounds and to compounds prepared by these methods. These compoundsmay have pharmaceutical activity, especially as phosphate binders. Thepresent invention further relates to novel mixed metal compounds. Yetfurther the invention relates to pharmaceutical compositions containingthe above compounds and to the pharmaceutical use of the compounds.

BACKGROUND OF THE INVENTION Hyperphosphataemia

Hyperphosphataemia is an electrolyte disturbance in which there is anabnormally elevated level of phosphate in blood. Hyperphosphataemia isfrequently seen in dialysis patients, as standard dialysis regimes areunable to remove the ingested phosphate load even with a low phosphatediet, and is associated with an increased risk of death and thedevelopment of vascular calcification. The presence ofhyperphosphataemia leads to hypocalcaemia, secondaryhyperparathyroidism, reduced 1.25 Vit D3 and progressive metabolic bonedisease Hyperphosphataemia is ultimately responsible for the increase invascular calcification, but recent studies have also suggested that theprocess may additionally be influenced by 1.25 Vit D3 and an elevatedcalcium-phosphate product. Patients who have chronically uncontrolledhyperphosphataemia develop progressively extensive soft tissuecalcifications due to the deposit of Calcium/phosphate product intoskin, joints, tendons, ligaments. Eye deposits of calcium/phosphateproduct have also been described.

Control of serum phosphate levels using oral phosphate binders has,therefore, become a key therapeutic target in the management of dialysispatients. These binders, taken with food, render the contained phosphateinsoluble and, therefore, non-absorbable,

Phosphate Binders

Historically phosphate binders included aluminium salts. However, use ofaluminium salts was found to result in further toxic complications dueto aluminium accumulation, e.g. reduction in haemoglobin production,impairment in natural repair and production of bone and possibleimpairment of neurological/cognitive function. Renal bone disease,osteomalacia and dementia are the most significant toxicities related tothe absorption of aluminium. Other aluminium compounds such asmicrocrystalline aluminium oxide hydroxide (boehmite) and certainhydrotalcites were proposed for this use, such as disclosed in Ookubo etal, Journal Pharmaceutical Sciences (November 1992), 81 (11), 1139-1140However these suffer from the same drawbacks.

Calcium carbonate or calcium acetate are used as phosphate binders.However these suffer from the drawback that they tend to promotehypocalcaemia through the absorption of high amounts of ingested calciumand are linked to accelerated cardiovascular calcification which cancause serious side effects. Consequently, frequent monitoring of serumcalcium levels is required during therapy with calcium-based phosphatebinders. The National Kidney Foundation Kidney Disease Quality OutcomesInitiative suggests the limited use of calcium based salts (ClinicalPractice Guidelines for Bone Metabolism and Disease in Chronic KidneyDisease, Guide 5, pg 1 pt 5.5) Recent efforts, therefore, have focusedon the development of phosphate binders free of calcium. More recently,lanthanum carbonate and sevelamer HCl have been used as calcium-freephosphate binders. Sevelamer hydrochloride is a water-absorbing,non-absorbed hydrogel-cross-linked polyallylamine hydrochloride butbecause of its structure also binds certain fat-soluble vitamins andbile acids and is therefore reported in V Autissier et al, Journal ofPharmaceutical Sciences, Vol 96, No 10, October 2007 to require largedoses to be effective because it has a higher propensity for the boundphosphate to be displaced by these competing anions. A high pill burdenor large tablets are often associated with poor patient compliance andthis type of product is also considered relatively expensive to theircalcium counter parts. Sevelamer has also been associated with GIadverse effects A. J. Hutchison et al, Drugs 2003; 63 (6), 577-596.

Lanthanum carbonate is a phosphate binder which has been shown to be aseffective as calcium carbonate with lower incidence of hypocalcaemia.Long-term administration of lanthanum, a rare earth element, continuesto raise safety concerns with regards to the potential accumulation of arare earth metal in body tissue which can be enhanced in renalfailure—Tilman B Druke, Seminars in Dialysis, Volume 20, Issue 4 page329-332 July/August 2007

Many known inorganic preparations for treatment of hyperphosphataemiaare efficient phosphate binders only over a limited pH range. Moreover,particularly alkaline binders could buffer the stomach pH up to a highlevel at which they would not have a phosphate binding capacity.

To overcome the drawbacks associated with aluminium and also problems ofefficacy over a limited pH range, WO-A-99/15189 discloses use of mixedmetal compounds which are free from aluminium and which have a phosphatebinding capacity of at least 30% by weight of the total weight ofphosphate present, over a pH range of from 2-8.

Mixed Metal Compounds

Mixed metal compounds (mixed metal compounds) exist as so-called“Layered Double Hydroxide” (LDH) which is used to designate synthetic ornatural lamellar hydroxides with two kinds of metallic cations in themain layers and interlayer domains containing anionic species. This widefamily of compounds is sometimes also referred to as anionic clays, bycomparison with the more usual cationic clays whose interlamellardomains contain cationic species. LDHs have also been reported ashydrotalcite-like compounds by reference to one of the polytypes of thecorresponding [Mg—Al] based mineral. (See “Layered Double Hydroxides:Present and Future”, ed, V Rives, 2001 pub. Nova Science).

By mixed metal compound, it is meant that the atomic structure of thecompound includes the cations of at least two different metalsdistributed uniformly throughout its structure. The term mixed metalcompound does not include mixtures of crystals of two salts, where eachcrystal type only includes one metal cation. Mixed metal compounds aretypically the result of coprecipitation from solution of differentsingle metal compounds in contrast to a simple solid physical mixture oftwo different single metal salts. Mixed metal compounds as used hereininclude compounds of the same metal type but with the metal in twodifferent valence states e.g. Fe(II) and Fe(III) as well as compoundscontaining more than two different metal types in one compound.

The mixed metal compound may also comprise amorphous (non-crystalline)material. By the term amorphous is meant either crystalline phases whichhave crystallite sizes below the detection limits of x-ray diffractiontechniques, or crystalline phases which have some degree of ordering,but which do not exhibit a crystalline diffraction pattern and/or trueamorphous materials which exhibit short range order, but no long-rangeorder.

Mixed metal compounds provide unique challenges in using inorganicmaterial for pharma use and in particular for phosphate binding andwhich are free of Al.

For example, use of mixed metal compound for attaining phosphatetherapeutic effects (or other pharma functional use) depends on surfaceprocesses such as physisorption (ion-exchange) and chemisorption(formation of a chemical bond) which is atypical for a drug; thetherapeutic activity of most drugs are based on organic compounds whichare typically more soluble.

Yet further, high daily and repeated long-term (chronic) dosages arerequired for kidney patients but their total daily pill count requires alow tablet burden due to restricted fluid intake Consequently, highdosage of drug substance is required in final product (e.g. tablet) andthe final product is therefore very sensitive to the properties of themixed metal compound drug substance, unlike normal formulations. Thismeans that the properties of the tablet, including key physicalproperties, and the tablet manufacturing processes, such as granulation,are often primarily influenced by the properties of the mixed metalcompound active substance rather than solely by those of the excipients.In order to be able to manufacture a pharmaceutical product comprisingsuch significant quantities of mixed metal compound with the control andconsistency necessary for pharmaceutical use, a means of controlling anarray of opposing chemical and physical properties of the mixed metalcompound is essential.

Therefore, considering these requirements, manufacture of suchmaterials, particularly at large scale, presents significant problems. Anumber of these problems are described below.

Ageing

The ageing process (growth of crystallites) generally increases with(unintended) increased processing and handling as well as by the processwhereby the crystallites are intentionally grown by a combination ofagitation and heat-treatment of the reaction slurry before filtrationControl and prevention of crystal growth can therefore be difficult.

The teachings of MgAl mixed metal compounds which are manufactured inthe aged form for medical applications such as antacids, do not addressthe problems of manufacture of unaged mixed metal compounds (on a largerscale), when the unaged form is required, for example to maintaintherapeutic activity of phosphate binding. Furthermore, when replacingAl for Fe we found that the mixed metal compound changes properties suchas to becoming more difficult to wash and mill on a commercial scale.

Al-containing mixed metal compounds that are intentionally aged toincrease crystal growth have previously been manufactured on a largescale. In contrast, there appear to be no examples of large scalemanufacture of unaged Al-free mixed metal compounds.

The method disclosed in WO99/15189 relates to Al free mixed metalcompounds and includes examples of unaged and aged materials. However,the products disclosed in this publication are provided at relativelysmall scale. WO99/15189 does not address the problems of provision ofproduct at significant scale while avoiding aging of the product.

The manufacture of unaged mixed metal Mg:Fe compounds (Mg:Fe defined bymolar ratio hereinafter) on a large scale is problematic for a number ofreasons. For example, the manufacture of unaged mixed metal Mg:Fecompounds is problematic when using conventional filtration methods.Unaged material results in a high pressure drop through the filter cakeduring isolation leading to low filtration rates or yield losses duringconventional filtration. Furthermore, these types of metal Mg:Fecompounds typically have small slurry particle size and as such it isdifficult to carry out isolation whilst minimising ageing. For example,small particles can give rise to increased processing times and/orhandling issues.

Furthermore, too much processing and handling (e.g. milling andoverdrying) can present changes that are unacceptable in the final mixedmetal Mg:Fe compound. In particular with such compounds, it is importantto dry the material carefully as it is easy to change the surface areaor internal pore volume and hence change the therapeutic activity. Thesetypical morphology properties are important characteristics affectingboth the quality of the final mixed metal compound and the downstreammanufacturing processes used to produce the final formulatedpharmaceutical product containing the mixed metal compound.

If processed incorrectly mixed metal compounds can become unacceptablyhard. This can lead to consequent issues of decreased milling rates andhigher energy input to achieve a given particle size. This ‘knock on’effect to the processing may affect process throughput and result inoverworking the material and consequential ageing.

Methods for lab-scale preparations of MgFe LDH's are disclosed in artsuch as U.S. Pat. No. 4,629,626; Duan X, Evans D. G., Chem. Commun.,2006, 485-496; W. Meng at al, J Chem. Sci., Vol. 117, No. 6 Nov. 2005,pp. 635-639; Carlino, Chemistry between the sheets, Chemistry inBritain, September 1997, pp 59-62; Hashi et al, Clays and Clay Minerals(1983) pp 152-15; Raki et al, 1995, 7, 221-224; Ookubo et al, Langmuir(1993), 9, pp 1418-1422I; Zhang et al. Inorganic Materials Vol 0.4 March132-138 (1997), Reichle, Solid States Ionics, 22, pp 135-141 (1986);Ulibarri at al, Kinetics of the Thermal Dehydration of some layeredHydrocycarbonates, Thermochimica Acta, pp 231-236 (1988); Hansen et al,Applied Clay Science 10 (1995) pp 5-19.

These methods describe lab-scale preparations only. Furthermore, thesematerials are obtained via a process which includes an ageing step (i.e.a deliberate process of increasing crystal growth which is typicallyachieved by heating the reaction slurry over a prolonged period of timesuch as by a hydrothermal process). In general, the compounds of theprior art also contain substantially more than one type of anion in theinterlayer region.

Methods for large scale manufacturing of MgAl hydrotalcites aredisclosed in art such as U.S. Pat. No. 3,650,704, WO-A-2008/129034 andWO-A-93/22237. However, these describe the process for obtainingmaterials in the aged form resulting in a larger crystallite size (ofabove 200 Angstrom) and are not free of aluminium.

Aspects of the invention are defined in the appended claims.

SUMMARY ASPECTS OF THE INVENTION

In one aspect the present invention provides a method of producing amixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å)comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 0 to 4.0 moles than is required to complete the        reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product.

In one aspect the present invention provides a method of producing amixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å)comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 2.0 to 4.0 moles than is required to complete the        reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product.

In one aspect the present invention provides a method of producing amixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å);the method comprising the step of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺+ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature between 15 and 30° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to less than 9.8, and wherein the Na₂CO₃ is provided at an            excess of greater than 1.0 to no greater than 5.0 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10, and wherein the Na₂CO₃ is provided at an            excess of greater than 1.0 to no greater than 4.0 moles than            is required to complete the reaction; or        -   (iii) wherein the pH of the slurry is maintained at from 9.5            to no greater than 10.1, and wherein the Na₂CO₃ is provided            at an excess of greater than 1.0 to no greater than 2.7            moles than is required to complete the reaction; or        -   (iv) wherein the pH of the slurry is maintained at from 9.5            to 10.5, and wherein the Na₂CO₃ is provided at an excess of            from greater than 1.0 to no greater than 2.0 moles than is            required to complete the reaction; or        -   (v) wherein the pH of the slurry is maintained at from            greater than 9.5 to no greater than 11, and wherein the            Na₂CO₃ is provided at an excess of from 0.0 to no greater            than 1.0 moles than is required to complete the reaction;            or the method comprising the step of:    -   (b) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature from 30 to 60° C., and:        -   (i) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 11, and wherein the Na₂CO₃ is            provided at an excess of greater than 0 to less than 2 moles            than is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 10.5, and wherein the Na₂CO₃            is provided at an excess of greater than 0 to less than 2.7            moles than is required to complete the reaction; or        -   (iii) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 10, and wherein the Na₂CO₃ is            provided at an excess of greater than 0 to less than 4 moles            than is required to complete the reaction.

In one aspect the present invention provides a method of producing amixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å),the method comprising the step of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature between 15 and 30° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to less than 9.8, and wherein the Na₂CO₃ is provided at an            excess of greater than 2.0 to no greater than 4.0 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10.3, and wherein the Na₂CO₃ is provided at an            excess of greater than 2.0 to less than 4.0 moles than is            required to complete the reaction; or        -   (iii) wherein the pH of the slurry is maintained at from            greater than 9.8 to no greater than 10.5, and wherein the            Na₂CO₃ is provided at an excess of greater than 1.0 to less            than 2.7 moles than is required to complete the reaction, or        -   (iv) wherein the pH of the slurry is maintained at greater            than 9.8 to less than 10.3, and wherein the Na₂CO₃ is            provided at an excess of from 1.0 to less than 4.0 moles            than is required to complete the reaction,            or the method comprising the step of:    -   (b) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature from 30 to 65° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to no greater than 10.5, and wherein the Na₂CO₃ is provided            at an excess of greater than 0 to less than 2.7 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10, and wherein the Na₂CO₃ is provided at an            excess of greater than 0 to less than 4 moles than is            required to complete the reaction.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺

having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å), wherein thecompound is obtained or obtainable by a method comprising the steps of

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 0 to 4.0 moles than is required to complete the        reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺

having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å), wherein thecompound is obtained or obtainable by a method comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 2.0 to 4.0 moles than is required to complete the        reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺

having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å), wherein thecompound is obtained or obtainable by a method comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature between 15 and 30° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to less than 9.8, and wherein the Na₂CO₃ is provided at an            excess of greater than 1.0 to no greater than 5.0 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10, and wherein the Na₂CO₃ is provided at an            excess of greater than 1.0 to no greater than 4.0 moles than            is required to complete the reaction, or        -   (iii) wherein the pH of the slurry is maintained at from 9.5            to no greater than 10.1, and wherein the Na₂CO₃ is provided            at an excess of greater than 1.0 to no greater than 2.7            moles than is required to complete the reaction; or        -   (iv) wherein the pH of the slurry is maintained at from 9.5            to 10.5, and wherein the Na₂CO₃ is provided at an excess of            from greater than 1.0 to no greater than 2.0 moles than is            required to complete the reaction; or        -   (v) wherein the pH of the slurry is maintained at from            greater than 9.5 to no greater than 11, and wherein the            Na₂CO₃ is provided at an excess of from 0.0 to no greater            than 1.0 moles than is required to complete the reaction            or by the method comprising the step of:    -   (b) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature from 30 to 60° C., and:        -   (i) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 11, and wherein the Na₂CO₃ is            provided at an excess of greater than 0 to less than 2 moles            than is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 10.5, and wherein the Na₂CO₃            is provided at an excess of greater than 0 to less than 2.7            moles than is required to complete the reaction; or        -   (iii) wherein the pH of the slurry is maintained at from            greater than 9.5 to less than 10, and wherein the Na₂CO₃ is            provided at an excess of greater than 0 to less than 4 moles            than is required to complete the reaction.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺

having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å), wherein thecompound is obtained or obtainable by a method comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature between 15 and 30° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to less than 9.8, and wherein the Na₂CO₃ is provided at an            excess of greater than 2.0 to no greater than 4.0 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10.3, and wherein the Na₂CO₃ is provided at an            excess of greater than 2.0 to less than 4.0 moles than is            required to complete the reaction; or        -   (iii) wherein the pH of the slurry is maintained at from            greater than 9.8 to no greater than 10.5, and wherein the            Na₂CO₃ is provided at an excess of greater than 1.0 to less            than 2.7 moles than is required to complete the reaction; or        -   (iv) wherein the pH of the slurry is maintained at greater            than 9.8 to less than 10.3, and wherein the Na₂CO₃ is            provided at an excess of from 1.0 to less than 4.0 moles            than is required to complete the reaction;            or by the method comprising the step of:    -   (b) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the slurry is maintained to a        temperature from 30 to 65° C., and:        -   (i) wherein the pH of the slurry is maintained at from 9.5            to no greater than 10.5, and wherein the Na₂CO₃ is provided            at an excess of greater than 0 to less than 2.7 moles than            is required to complete the reaction; or        -   (ii) wherein the pH of the slurry is maintained at from 9.5            to less than 10, and wherein the Na₂CO₃ is provided at an            excess of greater than 0 to less than 4 moles than is            required to complete the reaction.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å), and the d50 average particle size of the mixed metalcompound is less than 300 μm.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm, the average crystal size of the mixed metal compound is from 10 to20 nm (100 to 200 Å), and the water pore volume of the mixed metalcompound is from 0.25 to 0.7 cm³/g of mixed metal compound.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å), and the interlayer sulphate content of the compound isfrom 1.8 to 5 wt %.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å),and the interlayer sulphate content of the compound is from 1.8 to 3.2wt %.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is less than 20 nm(200 Å),and the interlayer sulphate content of the compound is from 1.8 to 5 wt%.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is less than 20 nm(200 Å), and the interlayer sulphate content of the compound is from 1.8to 3.2 wt %.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is less than 20 nm(200 Å),and the surface area is from 80 to 145 m² per gram of compound.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å),the surface area is from 40 to 80 m² per gram of compound.

In one aspect the present invention provides a mixed metal compound asdescribed herein for use as a medicament.

In one aspect the present invention provides a mixed metal compound asdescribed herein for binding phosphate.

In one aspect the present invention provides a mixed metal compound asdescribed herein for use in the treatment of hyperphosphataemia.

In one aspect the present invention provides a pharmaceuticalcomposition comprising a mixed metal compound as described herein andoptionally one or more pharmaceutically acceptable adjuvants,excipients, diluents or carriers.

Some Advantages

The present method provides a process which may be operated on a largescale to provide for a pharmaceutical phosphate binding drug ofconsistent composition which is stable upon storage and can be easilyformulated and/or packaged. Moreover, the present method provides forcontrol of key properties such as average crystal size, particle size,surface area, other morphology parameters (such as pore volume) anddegree of hydration—all of which are important for such manufacture.

Al-free mixed metal compounds containing Fe and Mg typically have aclay-like structure This presents limitations in view of the difficultfiltration of such products which in turn affect the viability of acontrolled process.

The present method provides a process which allows for manufacture of aconsistent ‘Al-free’ mixed metal compounds suitable for use in finalproduct formulations (e.g. tablet formulations etc). The therapeuticeffect of the final products and the ability to process the mixed metalcompounds into a final product consistently, depend on the physical(i.e. particle- and crystallite-size) and chemical (i.e. composition)properties of the mixed metal compound. The present process provides amethod for a consistent manufacture of pharmaceutical-grade ‘Al-free’mixed metal compounds with consistent particle- and crystallite-size.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺, wherein the molar ratio ofMg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1, the mixed metal compound has analuminium content of less than 10000 ppm, the average crystal size ofthe mixed metal compound is from 10 to 20 nm (100 to 200 Å), and theinterlayer sulphate content of the compound is from 1.8 to 5 wt % (suchas from 1.8 to 3.2 wt %).

For mixed metal compounds, maintaining the target metal molar ratio(Mg:Fe) during the reaction whilst meeting the above criteria isdifficult as this is affected by the way the material is processed. Wefound that correct stoichiometry is not only determined by the correctratios of the starting materials but also by pH for the reaction; i.e.when a pH is below pH 9.5 incomplete precipitation of magnesium mayoccur and too high a pH (i.e. above pH 11) risks loss of iron.

Mixed metal compounds can have more than one type of anion within theinterlayer region. This can introduce impurities which are undesirablewhen considering pharma use and we found can also affect therapeuticactivity (of phosphate binding). We have also found, surprisingly, thatthe type and amount of anions present in the interlayer region has amarked effect on the time taken to complete separation and washing ofthe unaged product, particularly for commercial scale manufacture. Forexample, we have found that at low (below 1.8% wt) interlayer sulphatelevels, separation and washing times increase significantly.

We found that when the amount of interlayer sulphate is maintained from1.8 to 5 wt % (such as from 1.8 to 3.2 wt %) phosphate binding of morethan 0.60 mmol phosphate/g compound can be obtained whilst maintaininglow filtration and wash times.

The combination of process parameters of the present method provides forthe preparation of mixed metal compounds which have controlled sulphate(SO₄) levels in the interlayer region.

Soluble SO₄ in the form of Na₂SO₄ salt can be readily removed by washingwhereas the interlayer sulphate cannot be removed by washing with water.

We found that the interlayer sulphate could be reduced withoutnecessarily increasing the filtration and wash times by reslurrying thedried compound in a solution containing carbonate enabling ion-exchange;however, this meant an additional reaction, isolation and drying stepand generally lead to a decrease in phosphate binding. Furthermore, thisroute would result in a longer overall time to manufacture. This routeto control interlayer sulphate is therefore less preferred.Alternatively, the interlayer sulphate may be reduced by washing orreslurrying the filtercake after isolation with a solution containingcarbonate instead of water Again this would lead to an additionalprocess step and is less preferred.

We found that by control of the process parameters as described herein,one may prepare a mixed metal compound having low levels of impurities,and in particular heavy metal impurities, without the need to performpurification to remove such impurities. The present invention mayprovide a process for preparing a mixed metal compound having a leadcontent of less than 1 ppm and/or a chromium content of less than 30 ppmand/or a total heavy metal content of less than 10 ppm and/or a sodiumcontent expressed as Na₂O of less than 0.5 wt %. In one aspect the mixedmetal compound has a total heavy metal content of less than 25 ppm,preferably less than 10 ppm. For example the present invention mayprovide a process for preparing a mixed metal compound having a totalheavy metal content of less than 15 ppm, a lead content less than 10ppm, a chromium level less than 35 ppm and a sodium content (expressedas Na₂O) of less than 1 wt %.

Heavy metals content as referred to herein are the group consisting ofAs, Cd, Pb, Hg, Sb, Mo and Cu Thus, reference to total heavy metalcontent will be understood to mean the combined content of As, Cd, Pb,Hg, Sb, Mo and Cu.

WO99/15189 teaches the preparation of a slurry at pH above 10 using a 5mole Na₂CO₃: 12 mole NaOH ratio which equates to an excess of 4 moleNa₂CO₃ than required to complete the reaction equation.

4MgSO₄+Fe₂(SO₄)₃+12NaOH+5Na₂CO₃->

Mg₄Fe₂(OH)₁₂CO₃ .nH₂O+7Na₂SO₄+4Na₂CO₃.

We have found that this excess of 4 mole Na₂CO₃ is not preferred,especially when precipitated at a pH of more than 10 and at roomtemperature. We found that this combination results in reducedsolubility of the carbonate in the reactant solution at the desiredreaction temperatures, provides poor filtration and wash times. We havefound that when preparing unaged material of 2:1 Mg:Fe molar ratioaccording to method of WO99/15189 that this material was more difficultto separate and wash when manufactured at scale whilst maintaining goodphosphate binding. This resulted in loss of batches as a result ofmaterial being out of specification.

Sodium carbonate not only provides the carbonate for the anion-exchangesites, but also acts as a pH buffer which assists pH control duringprecipitation. The ability to maintain an accurate precipitation pH isconsiderably increased when Na₂CO₃ is present. However, we have alsofound that the filtration rate significantly increases when Na₂CO₃ isreduced from a 2.7 mole excess to zero excess. A high filtration rate isadvantageous when seeking to manufacture an unaged form of the Mg Femixed metal compounds. Such materials can be difficult to filter. Alsodecreasing the Na₂CO₃ further, such as below the 2.7 mole excess, mayresult in less precise pH control as well as increasing the level ofsulphate anions present in the interlayer region. As a consequence ofthe above, we have identified that there is a complex interrelationshipbetween pH, mole excess Na₂CO₃ and the temperature at which the slurryis maintained, all of which are important to maintain good phosphatebinding and filtration and or wash times. In particular we havedetermined that in order to obtain phosphate binding above 0.60 mmolphosphate/g compound and maintain good filtration and wash time it ispreferred to produce a slurry, wherein a temperature is maintainedbetween 15 and 30° C.

-   -   (i) wherein the pH of the slurry is maintained at from 9.5 to        less than 9.8, and wherein the Na₂CO₃ is provided at an excess        of greater than 1.0 to no greater than 5.0 moles than is        required to complete the reaction; or    -   (ii) wherein the pH of the slurry is maintained at from 9.5 to        less than 10, and wherein the Na₂CO₃ is provided at an excess of        greater than 1.0 to no greater than 4.0 moles than is required        to complete the reaction; or    -   (iii) wherein the pH of the slurry is maintained at from 9.5 to        no greater than 10.1, and wherein the Na₂CO₃ is provided at an        excess of greater than 1.0 to no greater than 2.7 moles than is        required to complete the reaction; or    -   (iv) wherein the pH of the slurry is maintained at from 9.5 to        10.5, and wherein the Na₂CO₃ is provided at an excess of from        greater than 1.0 to no greater than 2.0 moles than is required        to complete the reaction; or    -   (v) wherein the pH of the slurry is maintained at from greater        than 9.5 to no greater than 11, and wherein the Na₂CO₃ is        provided at an excess of from 0.0 to no greater than 1.0 moles        than is required to complete the reaction.

Alternatively, a Mg²⁺ salt and a Fe³⁺ salt can be combined with Na₂CO₃and NaOH to produce a slurry, wherein the slurry is maintained to atemperature from 30 to 60° C.

-   -   (i) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 11, and wherein the Na₂CO₃ is provided at        an excess of greater than 0 to less than 2 moles than is        required to complete the reaction, or    -   (ii) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 10.5, and wherein the Na₂CO₃ is provided        at an excess of greater than 0 to less than 2.7 moles than is        required to complete the reaction, or    -   (iii) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 10, and wherein the Na₂CO₃ is provided at        an excess of greater than 0 to less than 4 moles than is        required to complete the reaction.

Furthermore, we have found that in order to avoid the presence ofadditional crystalline phases in the compound (i.e. phases other thanhydrotalcite-type as detected by powder X-ray Diffraction) it isnecessary to wash the product to such an extent that the unboundsulphate (SO₄) i.e. in form of sodium sulphate (Na₂SO₄) is maintainedbelow 1.5 wt % (when expressed as Na₂SO₄) and preferably less than 1 wt% (when expressed as SO₄). This conversely can only be achieved when asmall amount of the interlayer sulphate is maintained such as to enableeffective filtration and washing at commercial scale.

The present method is a co-precipitation process. Such processesencourage the formation of different crystalline phases in addition tothe hydrotalcite phase. For use as an active in pharmaceuticalformulations, there is the requirement to be able to identify andcontrol the phase of interest. The present method provides for thepreparation of mixed metal compounds which contain less of (or aresubstantially free of) any other crystalline phases as determined by theabsence of XRD diffraction lines except those attributed to ahydrotalcite phase. The hydrotalcite phase had the following diffractionX-ray diffraction analysis: dA (‘d’ spacings) 7.74*, 3.86*, 3.20, 2.62*,2.33*, 1.97*, 1.76, 1.64, 1.55*, 1.52*, 1.48, 1.44*, 1.40, of which thepeaks marked * are the eight most intense peaks typically seen in theunaged samples. The remaining five peaks are only resolved in morecrystalline samples, typically as a result of ageing.

In summary, we have found that a total process of production (fromreaction to drying) is provided such as to prevent growth of thecrystallite size (above average crystal size 200 Å) in order to maintainthe phosphate binding activity without significantly hindering theprocess of isolation and washing of the compound. This was achieved bycareful control of process conditions and a specific selection of thesame such as by controlling interlayer sulphate from 1.8 to 5 wt % (suchas from 1.8 to 3.2 wt %) which in turn can be controlled via selectionof excess Na₂CO₃, reaction pH and reaction slurry temperature.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺, wherein the molar ratio ofMg²⁺ to Fe³⁺ is 1.5:1 to 2.5:1, the mixed metal compound has analuminium content of less than 10000 ppm, the average crystal size ofthe mixed metal compound is from 10 to 20 nm (100 to 200 Å), and the d50average particle size of the mixed metal compound is less than 300 μm.We have found surprisingly that this unaged compound with such averagecrystal size range and with milled particle size less than 300 microns,has the advantages of good, controlled phosphate binding (above 0.80mmol phosphate/g compound) whilst maintaining low magnesium release(less than 0.2 mmol magnesium/g compound). Above 300 micron particlesize we have found that the phosphate binding decreases markedly andmagnesium release increases to above 0.2 mmol magnesium/g compound.

We have found that an average crystal size of the mixed metal compoundof less than 20 nm (200 Å) and high surface area (80-145 m²/g) can bemanufactured using a process comprising a short residence drying stepsuch that the resultant material has both small average crystal size andhigh surface area but also importantly has a higher phosphate bindingcapacity as well as a lower magnesium release when compared at similard50 average particle size to that of the low surface area (40-80 m²/g)material; even when the material is not milled further. The requirementfor no milling has the advantage of reduced processing steps. A furtheradvantage is that such material can be suitable for tabletting processeswithout the need for wet granulation. A further advantage is thatmaterial manufactured via the short residence route may be exposed totemperatures above 150° C. because the residence time (less than 5minutes) of the product in the dryer is generally too short to enableany decomposition of the compound.

The mixed metal compound having an average crystal size of from 10 to 20nm (100 to 200 Å) and surface area 40-80 m²/g has the benefit of goodstability in particular phosphate binding, on storage. This product hasthe additional benefit of providing a smaller tablet size (i.e less than500 mm³ for 500 mg compound) thereby improving tablet pill burden; aprevalent issue within the treatment of renal patients. The material ofsurface area 40-80 m²/g which required micronisation can be manufacturedat commercial scale, including milling of the material, with minimalimpact on aging of the material as reflected in maintaining a smallaverage crystal size of below 200 Å. If the crystallite size is lessthan 100 Å it presents difficulties in milling to small particle size offor example, problems with trace metal impurities, milling rate anddecomposition of the product and over-drying of the product. Furthermorean additional surprising benefit is that such materials also exhibit nosignificant reduction in the uptake rate of phosphate, despite the lowersurface areas. This facet can be important when considering suchmaterials for pharmaceutical applications in which the binding ofphosphate needs to be rapid such as renal care. We have found that thematerial described above bind 80% phosphate within 10 minutes (TestMethod 3).

As for the product of 10 to 20 nm (100 to 200 Å) average crystal sizeand 40-80 m²/g surface area, the product of low surface area and lowpore volume by water from 0.3 to 0.65 cm³/g has the additional benefitof providing a smaller tablet size (i.e. less than 500 mm³ for 500 mgcompound) thereby improving tablet pill burden; a prevalent issueswithin the treatment of renal patients. Furthermore a higher densitymaterial is more suitable for the manufacture by wet granulation ofcompact tablets.

If product is dried to less than 85 wt % dry solid content storageproblems may be observed because of water-desorption. If product isdried to less than 80 wt % dry solid content, milling may beproblematic. If product is dried to more than 99 wt % the phosphatebinding may be reduced. If product is too dry storage problems may alsobe observed because of water-adsorption. Therefore, in one embodiment,the product is dried such that it has 80 wt % to 99 wt % dry solidcontent, preferably 85 wt % to 99 wt %.

In one aspect the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺, wherein the molar ratio ofMg²⁺ to Fe³⁺ is 1.5:1 to 2.5:1, the mixed metal compound has analuminium content of less than 10000 ppm, the average crystal size ofthe mixed metal compound is from 10 to 20 nm (100 to 200 Å), and thewater pore volume of the mixed metal compound is from 0.3 to 0.65 cm³/gof mixed metal compound. Surprisingly we have found that this low porevolume compound has the advantage of good phosphate binding that isessentially unchanged upon storage over periods of up to years, makingit viable as a pharmaceutically active material. It may be expectedtypically that significantly higher pore volumes would be required toattain such stability.

As used herein, the term ‘water pore volume’ refers to the pore volumeas determined in accordance with Test Method 15.

For ease of reference, these and further aspects of the presentinvention are now discussed under appropriate section headings. However,the teachings under each section may be combined and are not necessarilylimited to each particular section,

Preferred Aspects

As discussed herein the present invention provides a method of producinga mixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å)comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 0 to 4.0 moles than is required to complete the        reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product.

It will be understood by one skilled in the art that by “average crystalsize” it is meant the crystal size as measured in accordance with TestMethod 2.

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the pH of theslurry is maintained at from 9.5 to 10.5. Preferably the pH of theslurry is maintained at from 9.5 to less than 10.1. Preferably the pH ofthe slurry is maintained at from 9.5 to less than 10. Preferably the pHof the slurry is maintained at from 9.5 to less than 9.8. Preferably thepH of the slurry is maintained at from 9.6 to 9.9. More preferably thepH of the slurry is maintained at approximately 9.8.

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the Na₂CO₃ isprovided at an excess from 2.0 to less than 4.0 moles, preferably at anexcess from 2.7 to less than 4.0 moles, preferably at an excess from 2.7to less than 3.2 moles, preferably at an excess from 2.7 to less than3.0 moles. More preferably the Na₂CO₃ is maintained at an excess ofapproximately 2.7 moles.

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the slurry ismaintained to a temperature between 15 and 30° C.

-   -   (i) wherein the pH of the slurry is maintained at from 9.5 to        less than 9.8, and wherein the Na₂CO₃ is provided at an excess        of greater than 1.0 to no greater than 5.0 moles than is        required to complete the reaction; or    -   (ii) wherein the pH of the slurry is maintained at from 9.5 to        less than 1.0, and wherein the Na₂CO₃ is provided at an excess        of greater than 1.0 to no greater than 4.0 moles than is        required to complete the reaction; or    -   (iii) wherein the pH of the slurry is maintained at from 9.5 to        no greater than 10.1, and wherein the Na₂CO₃ is provided at an        excess of greater than 1.0 to no greater than 2.7 moles than is        required to complete the reaction; or    -   (iv) wherein the pH of the slurry is maintained at from 9.5 to        10.5, and wherein the Na₂CO₃ is provided at an excess of from        greater than 1.0 to no greater than 2.0 moles than is required        to complete the reaction, or    -   (v) wherein the pH of the slurry is maintained at from greater        than 9.5 to no greater than 11, and wherein the Na₂CO₃ is        provided at an excess of from 0.0 to no greater than 1.0 moles        than is required to complete the reaction.

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the slurry ismaintained to a temperature between 15 and 30° C.

-   -   i) wherein the pH of the slurry is maintained at from 9.5 to        less than 9.8, and wherein the Na₂CO₃ is provided at an excess        of greater than 2.0 to no greater than 4.0 moles than is        required to complete the reaction; or    -   (ii) wherein the pH of the slurry is maintained at from 9.5 to        less than 10.3, and wherein the Na₂CO₃ is provided at an excess        of greater than 2.0 to less than 4.0 moles than is required to        complete the reaction; or    -   (iii) wherein the pH of the slurry is maintained at from greater        than 9.8 to no greater than 10.5, and wherein the Na₂CO₃ is        provided at an excess of greater than 1.0 to less than 2.7 moles        than is required to complete the reaction; or    -   (iv) wherein the pH of the slurry is maintained at greater than        9.8 to less than 10.3, and wherein the Na₂CO₃ is provided at an        excess of from 1.0 to less than 40 moles than is required to        complete the reaction;

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the slurry ismaintained to a temperature from 30 to 60° C.

-   -   (i) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 11, and wherein the Na₂CO₃ is provided at        an excess of greater than 0 to less than 2 moles than is        required to complete the reaction; or    -   (ii) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 10.5, and wherein the Na₂CO₃ is provided        at an excess of greater than 0 to less than 2.7 moles than is        required to complete the reaction; or    -   (iii) wherein the pH of the slurry is maintained at from greater        than 9.5 to less than 10, and wherein the Na₂CO₃ is provided at        an excess of greater than 0 to less than 4 moles than is        required to complete the reaction.

In one preferred aspect, in step (a) a Mg²⁺ salt and a Fe³⁺ salt arecombined with Na₂CO₃ and NaOH to produce a slurry, wherein the slurry ismaintained to a temperature from 30 to 65° C.

-   -   (i) wherein the pH of the slurry is maintained at from 9.5 to no        greater than 10.5, and wherein the Na₂CO₃ is provided at an        excess of greater than 0 to less than 2.7 moles than is required        to complete the reaction; or    -   (ii) wherein the pH of the slurry is maintained at from 9.5 to        less than 10, and wherein the Na₂CO₃ is provided at an excess of        greater than 0 to less than 4 moles than is required to complete        the reaction.

In one preferred aspect, in step (b) the slurry is subjected to mixingunder conditions providing a power per unit volume of 0.03 to 1.6 kW/m³.In one preferred aspect, in step (b) the slurry is subjected to mixingunder conditions providing a power per unit volume of 0.03 to 0.5 kW/m³.In one preferred aspect, in step (b) the slurry is subjected to mixingunder conditions providing a power per unit volume of 0.05 to 0.5 kW/m³

In one preferred aspect, in step (b) the slurry is controlled to a d50particle size distribution (psd) of at least 40 μm. Preferably, theslurry is controlled to a d50 psd of greater than 40 μm. Preferably, theslurry is controlled to a d50 psd of at least 50 μm Preferably, theslurry is controlled to a d50 psd of at least 60 μm. More preferably,the slurry is controlled to a d50 psd of at least 70 μm. Preferably, theslurry is controlled to a d50 psd of greater than 70 μm. The d50 psd ofthe slurry is as measured in accordance with Test Method 9 herein.

As used herein, the term ‘particle size distribution’ refers to the d50or average particle size distribution as determined in accordance withTest Method 24. D50 refers to the 50th percentile of that Test Method.

In one preferred aspect, in step (b) the slurry is controlled to a d50psd of at least 40 μm after the addition of the reactants and after aninitial hold time of 30 minutes to attain the optimum particle sizedistribution. Preferably, the slurry is controlled to a d50 psd of atleast 50 μm after the addition of the reactants and after an initialhold time of 30 minutes. Preferably, the slurry is controlled to a d50psd of at least 60 μm after the addition of the reactants and after aninitial hold time of 30 minutes. More preferably, the slurry iscontrolled to a d50 psd of at least 70 μm after the addition of thereactants and after an initial hold time of 30 minutes.

In one preferred aspect, the hold time of slurry before isolation, suchas before step (c), is less than 16 hours, preferably less than 12hours. Preferably, the hold time is more than 30 minutes. In onepreferred aspect, the hold time of slurry before isolation, such asbefore step (c), from 30 minutes to 16 hours. In one preferred aspect,the hold time of slurry before isolation, such as before step (c), from30 minutes to 12 hours. If hold time increases to more than 16 hours thecrystallite size may increase and/or particle size change.

In step (c) of the present method, the mixed metal compound is separatedfrom the slurry, to obtain a crude product having a dry solid content ofat least 10 wt %. Preferably the mixed metal compound is separated fromthe slurry, to obtain a crude product having a dry solid content of atleast 15 wt %. More preferably the mixed metal compound is separatedfrom the slurry, to obtain a crude product having a dry solid content ofat least 20 wt %.

In step (d) of the present method the crude product is dried either by

(i) heating the crude product to a temperature of no greater than 150°C. and sufficient to provide a water evaporation rate of 0.05 to 1.5 kgwater per hour per kg of dry product, or(ii) exposing the crude product to rapid drying at a water evaporationrate of 500 to 50000 kg water per hour per kg of dry product.

It will be understood by one skilled in the art that reference to“heating the crude product to a temperature of no greater than X° C.”refers to the heating the product such that the bulk temperature of theproduct is no greater than X° C. It will be understood that thetemperature to which the product is exposed, for example a drumtemperature in the case of drum drying, or the temperature of the shellof the product may be greater than X° C. when the bulk temperature ofthe product is X° C.

It will be understood by one skilled in the art that reference to awater evaporation rate at a rate of kg water per hour per kg of dryproduct, is to be measured in accordance with Test Method 18.

In one preferred aspect, step d(i) is followed, that is in step (d) thecrude product is dried by heating the crude product to a temperature ofno greater than 150° C. and sufficient to provide a water evaporationrate of 0.05 to 1.5 kg water per hour per kg of dry product.

In one preferred aspect, step d(ii) is followed, that is in step (d) thecrude product is dried by exposing the crude product to flash drying orspray drying at a water evaporation rate of 500 to 50000 kg water perhour per kg of dry product.

Preferably when step d(i) is followed, the crude product is dried byheating the crude product to a temperature of no greater than 150° C.and sufficient to provide a water evaporation rate of 0.05 to 1 kg waterper hour per kg of dry product, more preferably a water evaporation rateof 0.05 to 0.5 kg water per hour per kg of dry product, even morepreferably a water evaporation rate of 0.09 to 0.5 kg water per hour perkg of dry product, most preferred a water evaporation rate of 0.09 to0.38 kg water per hour per kg of dry product.

Preferably when step d(i) is followed, the crude product is dried byheating the crude product to a temperature of no greater than 150° C.,such as no greater than 140° C., such as no greater than 130° C., suchas no greater than 120° C., such as no greater than 110° C., such as nogreater than 100° C., such as no greater than 90° C., such as from 60 to150° C., such as from 70 to 150° C., such as from 60 to 140° C., such asfrom 70 to 140° C., such as from 60 to 130° C., such as from 70 to 130°C., such as from 60 to 120° C., such as from 70 to 120° C., such as from60 to 110° C., such as from 70 to 110° C., such as from 60 to 100° C.,such as from 70 to 100° C., such as from 60 to 90° C., such as from 70to 90° C. Preferably when step d(i) is followed, the crude product isdried by heating the crude product to a temperature of from 35 to 150°C., such as from 35 to 140° C., such as from 35 to 130° C., such as from35 to 120° C., such as from 35 to 110° C., such as from 35 to 100° C.,such as from 35 to 90° C., such as from 35 to 80° C., such as from 35 to70° C., such as from 35 to 60° C., such as from 35 to 50° C. Preferablywhen step d(i) is followed, the crude product is dried by heating thecrude product to a temperature of from greater than 40 to 150° C., suchas from greater than 40 to 140° C., such as from greater than 40 to 130°C., such as from greater than 40 to 120° C., such as from greater than40 to 110° C., such as from greater than 40 to 100° C., such as fromgreater than 40 to 90° C., such as from greater than 40 to 80° C., suchas from greater than 40 to 70° C., such as from greater than 40 to 60°C., such as from greater than 40 to 50° C. We have found that heatingthe crude product to a temperature of no greater than 90° C. andsufficient to provide a water evaporation rate of 0.05 to 1.5 kg waterper hour per kg of dry product is particularly preferred. In thisaspect, the average crystal size does not significantly increase duringdrying and the advantageous average crystal sizes described herein maybe provided

Preferably when step d(i) is followed, the crude product is dried byexposing the crude product to a temperature of no greater than 150° C.,preferably exposing the crude product to a temperature of no greaterthan 140° C., preferably exposing the crude product to a temperature ofno greater than 130° C., preferably exposing the crude product to atemperature of no greater than 120° C., preferably exposing the crudeproduct to a temperature of no greater than 110° C., preferably exposingthe crude product to a temperature of no greater than 100° C.,preferably exposing the crude product to a temperature of no greaterthan 90° C., preferably exposing the crude product to a temperature offrom 60 to 150° C., preferably exposing the crude product to atemperature of from 70 to 150° C., preferably exposing the crude productto a temperature of from 60 to 140° C., preferably exposing the crudeproduct to a temperature of from 70 to 140° C., preferably exposing thecrude product to a temperature of from 60 to 130° C., preferablyexposing the crude product to a temperature of from 70 to 130° C.,preferably exposing the crude product to a temperature of from 60 to120° C., preferably exposing the crude product to a temperature of from70 to 120° C., preferably exposing the crude product to a temperature offrom 60 to 110° C., preferably exposing the crude product to atemperature of from 70 to 110° C., preferably exposing the crude productto a temperature of from 60 to 100° C., preferably exposing the crudeproduct to a temperature of from 70 to 100° C., preferably exposing thecrude product to a temperature of from 60 to 90° C., preferably from 70to 90° C.

Preferably when step d(i) is followed, the crude product is dried tobetween 5-10 wt % moisture by exposing the crude product to atemperature from 35-90° C. and sufficient to provide a water evaporationrate of 0.05 to 0.5 kg water per hour per kg of dry product.

Preferably when step d(ii) is followed, the crude product is dried byexposing the crude product to flash drying or spray drying at a waterevaporation rate of 900 to 40000 kg water per hour per kg of dryproduct.

Preferably when step d(ii) is followed, the crude product is dried byexposing the crude product to flash drying at a water evaporation ratefrom 1500 to 50000 or exposing the product to spray drying at a waterevaporation rate from 500 to 1500 kg water per hour per kg of dryproduct. More preferably either from 20000 to 50000 by flash drying orfrom 900 to 1100 by spray drying.

Preferably when step d(ii) is followed, the crude product is dried byexposing the crude product to flash drying or spray drying at a waterevaporation rate of 500 to 50000 kg water per hour per kg of dryproduct, a delta T from 0.30 to 0.80 and residence time of product indryer of less than 5 minutes.

Before step (a) of the present method, after step (d) of the presentmethod, between any one of steps (a), (b), (c) and (d) of the presentmethod, one or more additional steps may be provided. These additionalsteps are encompassed by the present method. For example, in onepreferred aspect, the crude product is washed prior to step (d).

An additional process step according to one aspect of the presentinvention comprises performing ion exchange on the mixed metal compound.This may be performed at any time during the process, such as whenpresent in the slurry, as a crude product or a dried product. Apreferred ion exchange is in respect of sulphate present in the mixedmetal compound. Ion exchange performed in respect of sulphate present inthe mixed metal compound is preferably performed by exchanging sulphatewith carbonate, for example by contacting the mixed metal compound witha carbonate containing solution. Thus in this aspect, there is provideda method of producing a mixed metal compound comprising

at least Mg²⁺ and at least Fe³⁺having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å)comprising the steps of:

-   -   (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH        to produce a slurry, wherein the pH of the slurry is maintained        at from 9.5 to 11, and wherein the Na₂CO₃ is provided at an        excess of 0 to 4.0 moles (such as an excess of 2.0 to 4.0 moles)        than is required to complete the reaction    -   (b) subjecting the slurry to mixing under conditions providing a        power per unit volume of 0.03 to 1.6 kW/m³    -   (c) separating the mixed metal compound from the slurry, to        obtain a crude product having a dry solid content of at least 10        wt %    -   (d) drying the crude product either by        -   (i) heating the crude product to a temperature of no greater            than 150° C. and sufficient to provide a water evaporation            rate of 0.05 to 1.5 kg water per hour per kg of dry product,            or        -   (ii) exposing the crude product to rapid drying at a water            evaporation rate of 500 to 50000 kg water per hour per kg of            dry product,    -   (e) optionally contacting the slurry, the crude product or the        mixed metal compound, with a carbonate containing solution to        exchange sulphate present in the mixed metal compound with        carbonate.

The separation of the product may be performed by any suitable method.For example the mixed metal compound may be separated from the slurry bycentrifugation Different filtration methods may be utilized but apreferred aspect is obtained by a filtration method using centrifugationwhich combines filtration followed by washing and de-watering in onestep. Another preferred aspect is obtained by a filtration method usinga belt filter which combines filtration followed by washing andde-watering in one step

After step (d) the product may be further treated. The present inventionencompasses products obtained by virtue of further treatment. In oneaspect the dried crude product is classified by sieving to a d50 averageparticle size of less than 300 μm, more preferably the dried crudeproduct is milled to a d50 average particle size of less than 200 μm,more preferably the dried crude product is milled to a d50 averageparticle size of less than 100 μm, more preferably the dried crudeproduct is milled to a d50 average particle size of 2 to 50 μm, morepreferably the dried crude product is milled to a d50 average particlesize of 2 to 30 μm.

Preferably, as measured by sieving, less than 10% by weight of particlesare greater than 106 μm in diameter, more preferably less than 5%. Mostpreferably, no particles are greater than 106 μm in diameter as measuredby sieving.

After step d(i) the product may be further treated. The presentinvention encompasses products obtained by virtue of further treatment.In one aspect the dried crude product is milled. More preferably thedried crude product is milled to a d50 average particle size of lessthan 10 μm, yet more preferably the dried crude product is milled to ad50 average particle size from 2-10 μm. most preferred the dried crudeproduct is milled to a d50 average particle size from 2-7 μm, yet mostpreferred the dried crude product is milled to a d50 average particlesize of approximately 5 μm.

Preferably, after step d(i) the dried crude product is milled to providea surface area of 40-80 m²/g, more preferably to a surface area of 40-70m²/g, even more preferably to a surface area of 45-65 m²/g, mostpreferred to a surface area of 50-60 m²/g.

Preferably, after step d(i) the dried crude product is milled to a d50average particle size from 2-10 μm and a surface area of 40-80 m²/gcompound.

Preferably, after step d(ii) the dried product is not milled.Preferably, after step d(ii) the dried product has a d50 averageparticle size from 10-50 μm and a surface area of 80-145 m²/g compound.

Preferably the dried crude product has a water content of less than 15wt %, preferably the dried crude product has a water content of lessthan 10 wt %, preferably the dried crude product has a water contentfrom 1-15 wt %, preferably the dried crude product has a water contentfrom 5-15 wt %, preferably the dried crude product has a water contentfrom 5-10 wt %, preferably the dried crude product has a water contentfrom 8-15 wt %, preferably the dried crude product has a water contentfrom 8-11 wt %, based on the total weight of the dried crude product.

Preferably the mixed metal compound has a dry solid content of at least10 wt %. Preferably the mixed metal compound has a dry solid content ofat least 15 wt % More preferably the mixed metal compound has a drysolid content of at least 20 wt %.

When dried, the mixed metal compound has a dry solid content of at least80 wt %. Preferably, the dried mixed metal compound has a dry solidcontent of more than 85 wt %. Preferably the dried mixed metal compoundhas a dry solid content of less than 99 wt %, More preferably the driedmixed metal compound has a dry solid content of less than 95 wt %, Mostpreferred the dried mixed metal compound has a dry solid content from 90to 95 wt %.

As discussed herein, the compound has a average crystal size of lessthan 20 nm (200 Å) Preferably the compound has a average crystal size offrom 100 to 200 Å. Preferably the compound has a average crystal size offrom 155 to 200 Å. Preferably the compound has a average crystal size offrom 110 to 195 Å. Preferably the compound has a average crystal size offrom 110 to 185 Å. Preferably the compound has a average crystal size offrom 115 to 165 Å. Preferably the compound has a average crystal size offrom 120 to 185 Å. Preferably the compound has a average crystal size offrom 130 to 185 Å. Preferably the compound has a average crystal size offrom 140 to 185 Å Preferably the compound has a average crystal size offrom 150 to 185 Å Preferably the compound has a average crystal size offrom 150 to 175 Å. More preferably the compound has a average crystalsize of from 155 to 175 Å. More preferably the compound has a averagecrystal size of from 155 to 165 Å.

In a further preferred embodiment there is provided for the productionof a mixed metal compound having an average crystal size of less than 13nm (130 Å) and a phosphate binding capacity of more than 0.65 mmolphosphate/g mixed metal compound.

In a further preferred embodiment there is provided for the productionof a mixed metal compound having an average crystal size of less than 9nm (90 Å) and a phosphate binding capacity of more than 0.70 mmolphosphate/g mixed metal compound.

In one preferred aspect the present invention provides a mixed metalcomprising at least Mg²⁺ and at least Fe³⁺ wherein the molar ratio ofMg²⁺ to Fe³⁺ is 2.1:1 to 1.7:1 having an aluminium content of less than30 ppm, having a average crystal size from 110-195 Å, having aninterlayer sulphate from 2.1 to 5 wt % (such as from 2.1 to 3.2 wt %)comprising the steps of

(a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOH toproduce a slurry, wherein the pH of the slurry is maintained at from 9.6to less than 10, and wherein the Na₂CO₃ is provided at an excess of 2.7moles than is required to complete the reaction(b) subjecting the slurry to mixing under conditions providing a powerper unit volume of 0.05 to 0.05 kW/m³(b1) controlling the slurry to a temperature from 20 to 25° C.(b2) optionally controlling the slurry to a d50 psd of at least 40 μm(preferably controlling the slurry to a d50 psd of at least 40 μm)(c) separating the mixed metal compound from the slurry, to obtain acrude product having a dry solid content of at least 10 wt %(d) (i) drying the crude product to 5-10 wt % moisture by exposing thecrude product to a temperature from 40-90° C. and sufficient to providea water evaporation rate of 0.05 to 0.5 kg water per hour per kg of dryproduct.The compound prepared by the present method may be any mixed metalcompound comprising Me and at least Fe³⁺. In one preferred aspect, thecompound is a compound having a hydrotalcite structure. Preferably thecompound is of the formula

M^(II) _(1-x)M^(III) _(x)(OH)₂A^(n−) _(y) .mH₂O  (II)

wherein M^(II) is one or more bivalent metals and is at least Mg²⁺;M^(II) is one or more trivalent metals and is at least Fe³⁺;A^(n−) is one or more n-valent anions and is at least CO₃ ²⁻;1.0<x/Σyn<1.2, 0<x≦0.67, 0<y≦1 and 0<m≦10.

The method by which the molecular formula of a mixed metal compound maybe determined will be well known to one skilled in the art. It will beunderstood that the molecular formula may determined from the analysisof M^(II)/M^(III) ratio (Test Method 1), SO₄ analysis (Test Method 5),CO₃ analysis (Test Method 6) and H₂O analysis (Test Method 12).

Preferably, 0<x≦0.4, 0<y≦1 and 0<m≦10.

Preferably 1.05<x/Σyn<1.2, preferably 1.05<x/Σyn<1.15. In one preferredaspect x/Σyn=1.

In one preferred aspect 0.1<x, such as 0.2<x, 0.3<x, 0.4<x, or 0.5<x. Inone preferred aspect 0<x≦0.5. It will be understood thatx=[M^(III)]/([M^(II)]+[M^(III)]) where [M^(II)] is the number of molesof per mole of compound of formula I and [M^(III)] is the number ofmoles of M^(III) per mole of compound of formula I.

In one preferred aspect 0<y≦1. Preferably 0<y≦0.8. Preferably 0<y≦0.6.Preferably 0<y≦0.4. Preferably 0.05<y≦0.3. Preferably 0.05<y≦0.2.Preferably 0.1<y≦0.2. Preferably 0.15<y≦0.2.

In one preferred aspect 0≦m≦10. Preferably 0≦m≦8. Preferably 0≦m≦6.Preferably 0≦m≦4. Preferably 0≦m≦2. Preferably 0≦m≦1. Preferably0≦m≦0.7. Preferably 0≦m≦0.6. Preferably 0.1≦m≦0.6. Preferably 0.5≦m≦0.5.Preferably 0≦m≦0.3. Preferably 0≦m≦0.15 Preferably 0.15≦m≦0.5 The numberof water molecules m can include the amount of water that may beabsorbed on the surface of the crystallites as well as interlayer water.The number of water molecules is estimated to be related to x accordingto: m=0.81−x.

It will be appreciated that each of the preferred values of x, y, z andm may be combined.

In one preferred aspect the compound has an aluminium content of lessthan 5000 ppm, more preferably less than 1000 ppm, most preferred 100ppm, most preferably 30 ppm

In one preferred aspect the total sulphate content of the compound isfrom 1.8 to 5 wt % By total sulphate content it is meant content ofsulphate that is present in the compound. This may be determined by wellknown methods and in particular determined in accordance with TestMethod 1, Preferably the total sulphate is from 2 to 5 wt % preferablyfrom 2 to 3.7 wt %, preferably from 2 to 5 wt %, preferably from 2 toless than 5 wt %, preferably from 2.1 to 5 wt % preferably from 2.1 toless than 5 wt %, preferably from 2.2 to 5 wt %, preferably from 2.2 toless than 5 wt %, preferably from 2.3-5 wt %, preferably from 2.3 toless than 5 wt %.

In one preferred aspect the total sulphate content of the compound isfrom 1.8 to 4.2 wt %. By total sulphate content it is meant content ofsulphate that is present in the compound. This may be determined by wellknown methods and in particular determined in accordance with TestMethod 1. Preferably the total sulphate is from 2 to 4.2 wt % preferablyfrom 2 to 3.7 wt %, preferably from 2 to 3.2 wt %, preferably from 2 toless than 3.2 wt %, preferably from 2.1 to 3.2 wt % preferably from 2.1to less than 3.2 wt %, preferably from 2.2 to 3.2 wt %, preferably from2.2 to less than 3.2 wt %, preferably from 2.3-3.2 wt %, preferably from2.3 to less than 3.2 wt %.

The compound will also contain an amount of sulphate that is boundwithin the compound. This content of sulphate, the interlayer sulphate,may not be removed by a washing process with water. As used herein,amounts of interlayer sulphate are the amount of sulphate as determinedin accordance with Test Method 5. In a preferred aspect the interlayersulphate content of the compound is from 1.8 to 5 wt %, preferably from1.8 to 3.2 wt %, preferably from 2 to 5 wt %, preferably from 2 to lessthan 5 wt %, preferably from 2 to 3.2 wt %, preferably from 2 to 3.1 wt%, preferably from 2 to 3.0 wt %. Preferably the interlayer sulphatecontent of the compound is from 2.1 to 5 wt %, preferably from 2.1 to3.2 wt %, preferably from 2.1 to less than 3.2 wt %. More preferably theinterlayer sulphate content of the compound is from 2.2 to 5 wt %,preferably from 2.2 to 3.2 wt %, preferably from 2.2 to less than 3.2 wt%. Yet more preferably the interlayer sulphate content of the compoundis from 2.3 to 5 wt %, preferably from 2.3 to 3.2 wt %, preferably from2.3 to less than 3.2 wt %, Most preferably the interlayer sulphatecontent of the compound is from 2.5 to 5 wt %, preferably from 2.5 to3.2 wt %, preferably from 2.5 to less than 3.2 wt %. Yet most preferredthe interlayer sulphate content of the compound is from 2.5 to 3.0 wt %.

As discussed herein, the present invention provides novel compounds. Asdiscussed herein, the present invention provides a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å), and the d50 average particle size of the mixed metalcompound is less than 300 μm. Preferably the d50 average particle sizeof the mixed metal compound is less than 200 μm.

As discussed herein, the present invention provides a mixed metalcompound comprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5.1 to 1.5:1, the mixed metalcompound has an aluminium content of less than 10000 ppm, the averagecrystal size of the mixed metal compound is from 10 to 20 nm (100 to 200Å), and the water pore volume of the mixed metal compound is from 0.25to 0.7 cm³/g of mixed metal compound. Preferably the water pore volumeof the mixed metal compound is from 0.3 to 0.65 cm³/g of mixed metalcompound. Preferably the water pore volume of the mixed metal compoundis from 0.35 to 0.65 cm³/g of mixed metal compound Preferably the waterpore volume of the mixed metal compound is from 0.3 to 0.6 cm³/g ofmixed metal compound.

In further preferred embodiment of this aspect the nitrogen pore volumeof the mixed metal compound is from 0.28 to 0.56 cm³/g. As used herein,the term ‘nitrogen pore volume’ refers to the pore volume as determinedin accordance with Test Method 14. When the nitrogen pore volume of themixed metal compound is from 0.28 to 0.56 cm³/g it has been found thatthe close correlation to the water pore volume is such that the waterpore volume need not be determined. Thus in a further aspect the presentinvention provides a mixed metal compound comprising at least Mg²⁺ andat least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å), and the nitrogen pore volume of the mixed metal compoundis from 0.28 to 0.56 cm³/g.

As discussed herein, the present invention provides a mixed metalcompound comprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å),and the interlayer sulphate content of the compound is from 1.8 to 5 wt% (such as from 1.8 to 3.2 wt %). Preferably the average crystal size ofthe mixed metal compound is from 12 to 20 nm (120 to 200 Å).

As discussed herein, the present invention provides a mixed metalcompound comprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is less than 20 nm(200 Å),and the interlayer sulphate content of the compound is from 2.1 to 5 wt% (such as from 1.8 to 3.2 wt %). Preferably the average crystal size ofthe mixed metal compound is from 10 to 20 nm (100 to 200 Å).

As discussed herein, the present invention provides a mixed metalcompound comprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is less than 20 nm(200 Å), and the surface area is from 80 to 145 m² per gram of compound.Preferably the compound has a d50 average particle size of from 10 to350 μm (and preferably wherein the compound has not been subject tomilling). Preferably the compound has a d50 average particle size offrom 10 to 300 μm. Preferably the compound has a d50 average particlesize of from 10 to 210 μm. Preferably the compound has a d50 averageparticle size of from 10 to 100 μm. Preferably the compound has a d50average particle size of from 10 to 50 μm. Preferably the compound has ad50 average particle size of from 10 to 35 μm. Preferably the compoundreleases magnesium in an amount is less than 0.15 mmol magnesium/gcompound. The magnesium release is determined in accordance with TestMethod 3

As discussed herein, the present invention provides a mixed metalcompound comprising at least Mg²⁺ and at least Fe³⁺,

whereinthe molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1,the mixed metal compound has an aluminium content of less than 10000ppm,the average crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å),the surface area is from 40 to 80 m² per gram of compound.

Preferably the d50 average particle size of the mixed metal compound isless than 100 μm Preferably the d50 average particle size of the mixedmetal compound is less than 50 μm. Preferably the d50 average particlesize of the mixed metal compound is less than 20 μm. Preferably the d50average particle size of the mixed metal compound is less than 10 μm.Preferably the d50 average particle size of the mixed metal compound isapproximately 5 μm. Preferably the water pore volume of the mixed metalcompound is from 0.25 to 0.7 cm³/g of mixed metal compound, preferablythe water pore volume is from 0.3 to 0.65 cm³/g of mixed metal compound,preferably the water pore volume is from 0.3 to 0.6 cm³/g of mixed metalcompound. Preferably the nitrogen pore volume of the mixed metalcompound is from 0.28 to 0.56 cm³/g of mixed metal compound.

In each of the aspects of the invention in which a mixed metal compoundis provided, preferably

(1) the interlayer sulphate content of the compound is from 2.2 to 5 wt% (such as from 1.8 to 3.2 wt %), and/or(2) the compound is of the formula

M^(II) _(1-x)M^(III) _(x)(OH)₂A^(n−) _(y) .mH₂O

wherein M^(II) is one or more bivalent metals and is at least Mg²⁺,M^(III) is one or more trivalent metals and is at least Fe³⁺;A^(n−) is one or more n-valent anions and is at least CO₃ ²⁻,x/Σyn is from 1 to 1.2 (preferably x/Σyn is from 1.05 to 1.15,preferably x/Σyn is 1)0<x≦0.40<y≦1 and0<m≦10, and/or(3) the compound has an aluminium content of less than 100 ppm,preferably an aluminium content of fess than 30 ppm(4) the interlayer sulphate content of the compound is from 1.8 to 5 wt% (such as from 1.8 to 3.2 wt %), and/or(5) the compound has a d50 average particle size of less than 100 μm.preferably the compound has a d50 average particle size of 5 to 50 μm,preferably the compound has a d50 average particle size of approximately5 μm and/or(6) the water pore volume of the mixed metal compound is from 0.3 to0.65 cm³/g of mixed metal compound and/or(7) the compound has a dry solid content of at least 20 wt %.

The compound may have any degree of porosity, subject to any rangespecified herein. In a preferred aspect the water pore volume of themixed metal compound is from 0.25 to 0.7 cm³/g of mixed metal compound.In a preferred aspect the water pore volume of the mixed metal compoundis from 0.3 to 0.65 cm³/g of mixed metal compound

Preferably the mixed metal compound comprises at least some materialwhich is a Layered Double Hydroxide (LDH). More preferably, the mixedmetal compound of formula (I) is a layered double hydroxide. As usedherein, the term “Layered Double Hydroxide” is used to designatesynthetic or natural lamellar hydroxides with two different kinds ofmetallic cations in the main layers and interlayer domains containinganionic species. This wide family of compounds is sometimes alsoreferred to as anionic clays, by comparison with the more usual cationicclays whose interlamellar domains contain cationic species. LDHs havealso been reported as hydrotalcite-like compounds by reference to one ofthe polytypes of the corresponding [Mg—Al] based mineral

A particularly preferred mixed metal compound contains at least one ofcarbonate ions, and hydroxyl ions.

A particularly preferred compound contains as M^(II) and M^(III),magnesium and iron (III) respectively.

Process

The mixed metal compound or compounds may be suitably made byco-precipitation from a solution, followed by centrifugation orfiltration, then drying, milling and/or sieving. The mixed metalcompound may then be rewired as part of the wet-granulation process andthe resulting granules dried in a fluid-bed dryer. The degree of dryingin the fluid-bed is used to establish the desired water content of thefinal tablet.

Two methods of coprecipitation may be used, namely one at lowsupersaturation whereby the pH of the reaction solution is maintainedconstant by controlling the addition of a second solution of an alkali,or alternatively precipitation at high supersaturation whereby the pH ofthe reaction solution is continuously changed by addition of the mixedmetal solution to an alkali solution already present in the reactorvessel. The precipitation method whereby the pH is kept constant ispreferred as this avoids the formation of single metal compounds such asM(OH)₂ and/or M(OH)₃ phases instead of mixed metal compound.

Other precipitation methods of the mixed metal compound may also bepossible if the crystallite size is controlled to less than 200 Å. Forexample, a precipitation method involving separate nucleation and agingsteps, an urea hydrolysis method, an induced hydrolysis method, asalt-oxide method, a sol-gel method, an electrosynthesis method, an insitu oxidation of the divalent metal ion to a trivalent metal ion, aso-called “Chimie Douce” method or a method wherein the mixed metalcompound may be formed by heating an intimate mixture of finely dividedsingle metal salts at a temperature whereby solid-solid reaction canoccur, leading to a mixed metal compound formation.

Post synthesis methods that tend to promote ageing are less preferredbut may be used if crystallite size is controlled to less than 200 Å.Examples of possible post synthesis heat-treatment steps includehydrothermal, microwave and ultrasound.

A variety of methods can be used to separate the mixed metal compoundfrom the reaction slurry. Different washing, drying and milling methodsare also possible where crystallite size is less than 200 Å.

The substances of the invention prepared by treatment of a suitablestarting material as hereinbefore described may be prepared by providinga first solution of a water soluble compound of metal and a watersoluble compound of metal M^(III), the anions being chosen so as not toresult in precipitation from the first solution (A). A second solution(B) is also provided, of a water soluble hydroxide (e.g. NaOH) and awater soluble salt of anion A^(n−) (the cation being chosen so as not toprecipitate with the hydroxide or the anion with the metal from thehydroxide). The two solutions are then combined and the mixed metalcompound starting material is formed by co-precipitation. For example,Solution A is made up by dissolving magnesium sulphate and ferricsulphate in purified water Solution B is made up by dissolving sodiumcarbonate and sodium hydroxide in purified water. A heel of purifiedwater is added to a reactor, the solutions A and B are fed in a ratiocontrolled manner. After the product forms in the reactor it maycomprise solid crystalline material, usually also with the presence ofsome solid amorphous material. Preferably, at least some of the materialso formed is of a layered double hydroxide and/or of a hydrotalcitestructure, usually also with some amorphous and/or poorly crystallinematerial, preferably after co-precipitation, the material is thenfiltered or centrifuged, washed then dried by heating. The drying iscarried out either by (i) exposing the crude product to a temperature ofno greater than 150° C. and sufficient to provide a water evaporationrate of 0.05 to 1.5 kg water per hour per kg of dry product, or (ii)exposing the crude product to flash drying or spray drying at a waterevaporation rate of 500 to 50000 kg water per hour per kg of dryproduct, for example by oven drying, spray drying or fluid bed drying.

Optionally, the dry material may be first classified, to remove oversizeparticles by milling and/or sieving and/or any other suitable technique,for example to restrict the material to be treated to particles whichare substantially no greater than 300 μm in diameter.

Reaction

A wide number of options are available for carrying out the reaction.These may be controlled in order to carry out the reaction in the mannerdesired. For example, the reactant equipment type, reactant streamcomposition, temperature and pH, mode of reactant addition, agitationsystem, and hold time may all be specified in order to produce a desiredreaction.

Various reactor types are common in the pharmaceutical industry, theseinclude Batch and Continuous reactors.

The material structure and crystallite size can be significantlydetermined at the reaction stage by close control of the reactantsolution concentration, the reaction temperature, the time that thereaction mass is held following precipitation and the mode of reactantaddition. Furthermore, in order to achieve the preferred materialstructure with small crystallite size, a high solution concentration (atend of reaction period of 4.8-5.4 wt %), low reaction temperature(15-25° C.) and short hold time (typically <12 hours) are preferred

To prepare the mixed metal compounds to a preferred Mg:Fe molar ratio,for example from 1.5:1 to 2.5:1 then precise control of pH during theprecipitation process is desirable. Precise pH control is typicallyachieved by frequent calibration of pH electrodes and monitoring andadjustment of the pH throughout the precipitation process. The pH of thereaction may be controlled by varying the relative rate of addition ofSolution A to Solution B added to the reactor. We have found that thevariation of Solution B only is preferred since this maintains theprecipitate concentration in the reaction mix at a constant level. Thevariation in Solution B flow rate can be carried out manually or using asuitable control algorithm.

We have found an optimal reactant composition, whereby opposingrequirements of maintaining a relatively low reaction temperature, butachieving reasonable filtration rate and good pH control, are met.

For example, the preferred M²⁺:M³⁺ molar ratio between 1.5:1 to 2.5:1 ofthe mixed metal compound can be achieved by maintaining the reactantstreams in solution even at relatively low temperatures, therebylimiting the reaction temperature. The reaction temperature can beimportant in determining the extent of crystallite growth and hence thephosphate binding activity.

The preferred method allows good filtration rates to be achieved, thisagain can be important in limiting the reaction mass storage time whichin term is known to help determine the extent of crystallite growth, andhence the phosphate binding activity

Further, the preferred reaction conditions and recipe helps to maintaingood pH control Good pH control is required in order to achieve thetarget pH

The mode of reactant stream addition can be important in defining thereaction product quality. Different combinations of addition mode arepossible and may include the addition of one reactant stream into anexcess of the other reactant (either reactant could be selected as theadded stream).

We have found that simultaneous addition of a high pH reactant streamcontaining carbonate and hydroxide ions, and a low pH reactant streamcontaining metal and sulphate ions into a heel provides more accurate pHcontrol of the reaction slurry. Therefore, in a preferred embodiment,the reaction is carried out by simultaneous addition (co-precipitation)of a reactant stream containing carbonate and hydroxide ions, and areactant stream containing metal and sulphate ions.

Similarly, the product can be removed on a continuous basis as thereactant streams are added, or at the end of a defined period.

Good filtration characteristics are achieved by targeting a relativelylarge particle size such as of at least 40 μm by controlling the powerper unit volume from 0.03 to 1.6 kW/m³. We have identified that powerper unit volume of 0.05 to 0.5 kW/m³ using impeller(s) configured foraxial flow agitation, helps to produce a slurry with further improvedfiltration characteristics (such as lower filtration and washing time,and high final solids content in cake).

Therefore, in a preferred embodiment, agitation is used to subject theslurry to mixing under conditions providing a power per unit volume of0.03 to 1.6 kW/m³ provided by static mixers, impeller agitators, pump,jet mixer or dynamic in line mixer. Therefore, in a further preferredembodiment, axial flow agitation is used to subject the slurry to mixingunder conditions providing a power per unit volume of 0.03 to 1.6 kW/m³provided by an impeller agitator. More preferably a power per unitvolume of 0.05 to 0.5 kW/m³ delivered by impeller agitation. Thisprovides reaction slurry with the preferred filtration characteristics.

Therefore, in a separate embodiment, the reaction is agitated usingmeans other than a conventional impeller agitator.

An optimum hold time has been identified as from 30 minutes to 12 hours.For hold times of more than 16 hours, filtration becomes difficult dueto a reduction in particle size during use of agitation in hold time andageing occurs.

Filtration

A wide number of options are available for carrying out the productisolation and washing steps, however the filtration equipment type andoperating process parameters should be carefully defined and controlled

For example, in order to limit the overall reaction slurry hold time(and hence crystallite growth), it is beneficial to minimise the timefor cake isolation and wash time A high cake solids content is alsopreferable as this reduces the drying time and hence the propensity forcrystallite growth during the drying step.

Various filter types are used in the pharmaceutical industry, theseinclude: Neutsche filters, Filter dryers, Filtering centrifuges, Beltfilters, Plate and frame filters.

When isolating the unaged mixed metal compound, the overall filtrationrate can be extremely low due to the relative difficulty of isolatingand washing these unaged clay-type mixed metal compounds making thiseconomically unattractive if not controlled to the preferred conditions.The unaged material of crystallite size of less than 200 Å, has thetendency to result in ‘blinding’ of the filtration media and/or theclay-type properties have a tendency to form a more impermeable cake.

In one preferred embodiment we have produced high filtration rate usinga belt filter

Drying

A wide number of options are available for carrying out the dryingoperation, these should be defined and controlled in order to carry outthe drying step in the best manner.

For example, the dryer type, mode of drying, and rate of drying shouldbe specified and controlled such that the crude product is dried eitherby (i) exposing the crude product to a temperature of no greater than150° C. and sufficient to provide a water evaporation rate of 0.05 to1.5 kg water per hour per kg of dry product, or (ii) exposing the crudeproduct to flash drying or spray drying at a water evaporation rate of500 to 50000 kg water per hour per kg of dry product. The rate of dryingis affected by factors including the mode of drying, heatedsurface/heating medium temperature, degree of agitation, vacuum level(if any) etc. The product temperature must be limited to no greater than150° C. to prevent damage to the drug substance.

Various dryer types are common in the pharmaceutical industry, theseinclude long residence time dryers (characterised as typically up to 20h residence time) such as Spherical, Conical, Double cone, Tray dryer(vacuum, ambient pressure), and short residence time dryers(characterised as typically up to several minutes residence time)include; Spray, Spin flash, Etc.

We have found that of the various batch dryer designs an agitatedspherical dryer offers a large heated surface area to the product.Therefore a higher product rate per unit area from 1 to 2.1 kgproduct/(m² hr) and thus high heat transfer and drying rates arepossible. Since ageing (crystallite growth) can occur during drying, itis important to minimise the drying time/maximise drying rate. In orderto prevent decomposition of the drug substance, where surface heating isused the drying surface temperature is typically limited to 150° C. forbatch drying and preferably 90° C. or less to avoid average crystal sizegrowth to above 200 Å. Partial evacuation of the dryer depresses theboiling point of water in the drying mass, thereby limiting crystalgrowth, this depression also serves to maximise the drying rate. Thedrying rate is manipulated by maximising the dryer vacuum and/orincreasing the shell temperature up to 120° C. during an initial dryingphase, to remove water at the highest possible rate, and then reducingthe rate by reducing the shell temperature to less than 90° C., in orderto accurately target a defined moisture end point whilst maintaining acrystallite size less than 200 Å. The moisture end point can be inferredby monitoring the evaporation mass, or measured directly, by analysis ofthe dried contents, or other suitable methods

Conical dryers (e.g. Nautamixer type) offer similar benefits to thespherical dryer

Vacuum tray dryers were found to produce an acceptable product quality,however this type of dryer can require manual intervention (e.g.redistribution of solids) for uniform drying, and has limitedthroughput.

The long residence time batch dryers described (spherical, conical,vacuum) all have relatively low drying rates (expressed in normalisedterms as kg evaporation per kg product per hour) when compared to theshort residence time drying methods We have found that the temperatureof the drug substance during drying and the drying rate cansignificantly influence the crystallite size and morphology of the drugsubstance

For example, long residence time batch drying tends to produce arelatively large average crystal size and relatively low pore volume andsurface area, whereas short residence methods such as spray drying andspin flash drying have been found to produce relatively smaller crystalswith relatively large pore volume and surface area. Material producedusing short residence time drying can show an enhanced phosphate bindingperformance; this may be due to the different crystallite andmorphological properties. Spray dried material has the additionaladvantage of granulation for just dry blending (e.g. for tabletmanufacture) and may be carried out without prior milling of the drugsubstance.

Long residence drying time methods are typically defined as having aresidence time equal to or greater than 3 hours. Examples of theseinclude: tray drying, kettle drying, pan drying, rotary (shell) drying,rotary (internal) drying, double cone drying.

We have found average evaporation rates of between 9 and 29 kgwater/(h·m²) are achievable using an agitated vacuum spherical dryer.Stated on an alternative basis this is equivalent to an evaporation rateof approximately 0.05 to 0.5 kg water per hour per kg of dry product.The product crystallite size produced at this range of evaporation ratesis typically between 100-200 Angstroms. For a dried product ofconsistent quality the dryer must be fed with a wet cake (typically >20wt % solids).

Each of the above dryers is operated on a batch basis.

Short residence drying time method examples typically have much lowerresidence times. These differ depending upon technology types and aredefined as: spin flash drying, typical residence time of 5 to 500seconds/spray drying, typical residence time up to 60 seconds.

Typical evaporation rates are defined as spin flash 70-300 kgwater/(h·m³) vessel volume, spray 5-25 kg water/(h·m³) vessel volume.Evaporation rates for spin flash and spray dryers are also calculated as500 to 50000 kg water/(h kg drug). The product crystallite size producedat this range of evaporation rates is typically less than 140 Angstroms.The spin flash dryer may be fed with wet cake (typically >20 wt %solids), whereas the spray dryer must be fed with a free flowing slurryat a lower concentration (typically to 10 wt % solids)

The above short residence time dryers may all be operated on acontinuous basis.

Various ‘medium’ residence time technologies can be used whichpredominantly rely on the use conveyors and are operated continuously.These may be less preferred if problems occur in terms of ensuring aconsistent quality of product (variable moisture content) andcleanliness for pharmaceutical production. Examples of medium residencetime technologies are listed as: Rotary shelf, Trough Vibrating, Turbotype.

Uses

Preferably the compound is used in the manufacture of a medicament forthe prophylaxis or treatment of hyperphosphataemia.

In a further aspect the present invention provides use of a compound ofthe present invention or obtained/obtainable in accordance with thepresent invention in the manufacture of a medicament for the prophylaxisor treatment of any one of hyperphosphataemia, renal insufficiency,hypoparathyroidism, pseudohypoparathyroidism, acute untreatedacromegaly, chronic kidney disease and over medication of phosphatesalts.

Examples of one or more of the symptoms which may indicate risk for thepresence of CKD: a creatine concentration of above 1.6 mg/dL, a bloodphosphate level of above 4.5 mg/dL, any detectable blood in urine, urineprotein concentration above 100 mg/dL, a urine albumin concentrationabove about 100 mg/dL, a glomerular filtration rate (GFR) of below 90mL/min/1.73 m² or a parathyroid hormone concentration in the blood above150 pg/mL. The symptoms are also defined by the National KidneyFoundation-Sidney Disease Outcomes Quality Initiative “NKF-K/DOQI” or“K/DOQI,”.

In one preferred aspect the chronic kidney disease (CKD) treated inaccordance with the presence invention is CKD having stage one to five.

The medicament may be used on animals, preferably humans.

Pharmaceutical Compositions

A pharmaceutically acceptable carrier may be any material with which thesubstance of the invention is formulated to facilitate itsadministration. A carrier may be a solid or a liquid, including amaterial which is normally gaseous but which has been compressed to forma liquid, and any of the carriers normally used in formulatingpharmaceutical compositions may be used. Preferably, compositionsaccording to the invention contain 0.5% to 95% by weight of activeingredient. The term pharmaceutically acceptable carrier encompassesdiluents, excipients or adjuvants.

When the substances of the invention are part of a pharmaceuticalcomposition, they can be formulated in any suitable pharmaceuticalcomposition form e.g. powders, granules, granulates, sachets, capsules,stick packs, battles, tablets but especially in a form suitable for oraladministration for example in solid unit dose form such as tablets,capsules, or in liquid form such as liquid suspensions, especiallyaqueous suspensions or semi-solid formulations, e.g. gels, chewy bar,dispersing dosage, chewable dosage form or edible sachet Direct additionto food may also be possible

Dosage forms adapted for extra-corporeal or even intravenousadministration are also possible. Suitable formulations can be producedby known methods using conventional solid carriers such as, for example,lactose, starch or talcum or liquid carriers such as, for example,water, fatty oils or liquid paraffins. Other carriers which may be usedinclude materials derived from animal or vegetable proteins, such as thegelatins, dextrins and soy, wheat and psyllium seed proteins; gums suchas acacia, guar, agar, and xanthan; polysaccharides, alginates;carboxymethylcelluloses, carrageenans; dextrans; pectins; syntheticpolymers such as polyvinylpyrrolidone, polypeptide/protein orpolysaccharide complexes such as gelatin-acacia complexes, sugars suchas mannitol, dextrose, galactose and trehalose, cyclic sugars such ascyclodextrin; inorganic salts such as sodium phosphate, sodium chlorideand aluminium silicates; and amino acids having from 2 to 12 carbonatoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid,L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

Auxiliary components such as tablet disintegrants, solubilisers,preservatives, antioxidants, surfactants, viscosity enhancers, colouringagents, flavouring agents, pH modifiers, sweeteners or taste-maskingagents may also be incorporated into the composition Suitable colouringagents include red, black and yellow iron oxides and FD & C dyes such asFD & C blue No. 2 and FD & C red No 40 available from Ellis & EverardSuitable flavouring agents include mint, raspberry, liquorice, orange,lemon, grapefruit, caramel, vanilla, cherry and grape flavours andcombinations of these. Suitable pH modifiers include sodiumhydrogencarbonate, citric acid, tartaric acid, hydrochloric acid andmaleic acid. Suitable sweeteners include aspartame, acesulfame K andthaumatin. Suitable taste-masking agents include sodiumhydrogencarbonate, ion-exchange resins, cyclodextrin inclusioncompounds, adsorbates or microencapsulated actives.

For treatment of and prophylaxis of hyperphosphataemia, preferablyamounts of from 0.1 to 500, more preferably from 1 to 200, mg/kg bodyweight of substance of the invention as active compound are administereddaily to obtain the desired results. Nevertheless, it may be necessaryfrom time to time to depart from the amounts mentioned above, dependingon the body weight of the patient, the method of application, the animalspecies of the patient and its individual reaction to the drug or thekind of formulation or the time or interval in which the drug isapplied. In special cases, it may be sufficient to use less than theminimum amount given above, whilst in other cases the maximum dose mayhave to be exceeded. For a larger dose, it may be advisable to dividethe dose into several smaller single doses, Ultimately, the dose willdepend upon the discretion of the attendant physician. Administrationsoon before meals, e.g. within one hour before a meal or taken with foodwill usually be preferred

A typical single solid unit dose for human adult administration maycomprise from 1 mg to 1 g, preferably from 10 mg to 800 mg of substanceof the invention.

A solid unit dose form may also comprise a release rate controllingadditive. For example, the substance of the invention may be held withina hydrophobic polymer matrix so that it is gradually leached out of thematrix upon contact with body fluids. Alternatively, the substance ofthe invention may be held within a hydrophilic matrix which gradually orrapidly dissolves in the presence of body fluid. The tablet may comprisetwo or more layers having different release properties. The layers maybe hydrophilic, hydrophobic or a mixture of hydrophilic and hydrophobiclayers. Adjacent layers in a multilayer tablet may be separated by aninsoluble barrier layer or hydrophilic separation layer. An insolublebarrier layer may be formed of materials used to form the insolublecasing. A hydrophilic separation layer may be formed from a materialmore soluble than the other layers of the tablet core so that as theseparation layer dissolves the release layers of the tablet core areexposed.

Suitable release rate controlling polymers include polymethacrylates,ethylcellulose, hydroxypropylmethylcellulose, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, sodiumcarboxymethylcellulose, calcium carboxymethylcellulose, acrylic acidpolymer, polyethylene glycol, polyethylene oxide, carrageenan, celluloseacetate, zein etc.

Suitable materials which swell on contact with aqueous liquids includepolymeric materials include from cross-linked sodiumcarboxymethylcellulose, cross-linked hydroxypropylcellulose, highmolecular weight hydroxypropylcellulose, carboxymethylamide, potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate,cross-linked polyvinylpyrrolidone and high molecular weightpolyvinylalcohols.

Solid unit dose forms comprising a substance of the invention may bepackaged together in a container or presented in foil strips, blisterpacks or the like, e.g. marked with days of the week against respectivedoses, for patient guidance.

There is also a need for formulations which could improve patientcompliance, for example in case of elderly or pediatric patients Aformulation in powder dose form could be either diluted in water,reconstituted or dispersed,

Combinations

The compound of the present invention may be used as the sole activeingredient or in combination with another phosphate binding agent. Itmay also be used in combination with a calcimimetic such as cinacalet,vitamin D or calcitriol

In a further aspect the present invention provides use of a compound ofthe present invention or obtained/obtainable in accordance with thepresent invention in the manufacture of a medicament for the prophylaxisor treatment of hyperphosphataemia.

EXAMPLES

General description of reaction.

The mixed metal compound is formed by the reaction of an aqueous mixtureof magnesium sulphate and ferric sulphate with an aqueous mixture ofsodium hydroxide and sodium carbonate. The precipitation is carried outat a pH of around 9.8 and a reaction temperature starting at around 22°C. and rising to up to 30° C. upon addition of reactants. The resultingprecipitate is filtered, washed, dried and milled.

The synthesis reaction is represented thus.

4MgSO₄+Fe₂(SO₄)₃+12NaOH+(XS+1)Na₂CO₃→Mg₄Fe₂(OH)₁₂.CO₃.nH₂O+7Na₂SO₄+XSNa₂CO₃

This generates a mixed metal compound with a molar ratio of Mg:Fe oftypically 2:1 and the reaction by-product sodium sulphate. Excess (XS)sodium carbonate added to the reaction mixture along with the sodiumsulphate is washed out of the precipitate.

By changing the molar ratio of M^(II):M^(III) cations to 1:1, 2:1, 3:1,4:1 different composition materials were achieved. The excess sodiumcarbonate and reaction pH were also changed in separate experiments

The molecular formula of layered double hydroxides can be measured bydifferent methods. The actual method used to determine the molecularformula of the examples herein was determined from the analysis ofM^(II)/M^(III) ratio (Method 1), SO₄ analysis (Method 5), CO₃ analysis(Method 6) and H₂O analysis (Method 12), Formula [M^(II) _(1-x)M^(III)_(x)(OH)₂][(CO₃)_(y1)(SO₄)_(y2).mH₂O][Na₂SO₄]_(z) was used to describethe composition of the examples (1-66) shown herein below in furtherdetail for mixed metal compound wherein:

x=[M^(III)]/([M^(II)]+[M^(III)]) where [M^(II)] is the number of molesof bivalent metal M^(II) per mole of compound of formula I and [M^(III)]is the number of moles of trivalent metal M^(III) per mole of compoundof formula I.Σy′=sum of the moles interlayer anions y1′ (CO₃ ²⁻)+y2′(SO₄ ²⁻) or anyother anions whereiny1′=wt % CO₃ ²⁻/Mw CO₃ ²⁻y2′=(wt % SO₄ ²⁻total/Mw SO₄ ²⁻)−(wt % Na₂O/Mw Na₂O)

Interlayer anions are also defined as bound anions or anions that cannotbe removed by washing with water.

Σy=Σy′*f

Σy=is the sum of moles interlayer anion corrected with the formulanormalisation factor (f).

y1=y1′*f

y2=y2′*f

f=x/(2*wt % M^(III) ₂O₃/MwM^(III) ₂O₃)=formula normalisation factor

m′=wt % H₂O/(Mw H₂O)

m=m′*f

wt % H₂O=LOD(loss on drying measured at 105° C.)

z=z′*f z=amount of sulphate remaining that can be removed by washing andis calculated from the amount of Na₂O the total of which is assumed tobe associated with SO₄ ²⁻ as soluble Na₂SO₄

z′=wt % Na₂O/Mw Na₂O

The ratio x/Σyn can be calculated from the values of x and the sum ofinterlayer anions (Σyn) the data for which is inserted below intomolecular formula[Mg_(1-x)Fe_(x)(OH)₂][(CO₃)_(y1)(SO₄)_(y2)mH₂O].[Na₂SO₄]_(z).

Example 1

Prepared by the method described below for preparation of approximately250 gram of dried product targeted to have a Mg:Fe molar ratio of 1:1.

The actual molecular formula found by analysis was:

[Mg₀₅Fe₀₅(OH)₂][(CO₃)₀₁₄(SO₄)₀₀₂.0.4H₂O][Na₂SO₄]₀₀₀

Wherein x=0.5, y1=0.14, y2=0.02, m=0.4, z=0.

Two starting materials, designated solution 1 and solution 2 wereprepared by the method set out below such as to provide an Na₂CO₃ excessof 2.7 mole (in reaction equation 1).

Magnesium sulphate and iron sulphate were dissolved in AnalaR™ water toprepare solution 1. In a separate vessel sodium carbonate and sodiumhydroxide were dissolved in AnalaR™ water to prepare solution 2. Theweights used were calculated to give the desired ratio of metal cations.

For the preparation of solution 1, AnalaR™ water was weighed out into avessel and stirred using an overhead mixer, into which was dissolved anappropriate amount of ferric sulphate hydrate (GPR grade). Oncedissolved, magnesium sulphate (Epsom Salt) was quantitativelytransferred to the stirred iron sulphate solution and allowed todissolve.

For the preparation of solution 2, AnalaR™ water was weighed out into avessel and stirred using an overhead mixer, into which was dissolved anappropriate amount of sodium carbonate (Pharmakarb). Once dissolved,sodium hydroxide (Pearl Caustic Soda) was quantitatively transferred tothe stirred sodium carbonate solution and allowed to dissolve

The solutions were then added simultaneously to stirred heel water of1100 cm³ at controlled flow rates sufficient to maintain pH 10.3 in thereaction mixture (+/−0.2 pH units) at a reaction temperature notexceeding 30° C. The final slurry concentration was around 5.1 wt %compound.

When the additions were complete, the reaction mixture was mixed foranother 30 minutes and then filtered using a buchner filtration set up.The product slurry was filtered using a vacuum pump and buchner funnelwith a Whatman™ hardened ashless filter paper (No 541). After filtering,the filter cake was washed with portions of Anala™ water.

The filtered product was then washed with 220 cm³ portions of coldAnalaR™ water. After isolation the product was dried using a preheatedoven.

A weight of AnalaR™ water was placed into a vessel. Flow control unitswere used to deliver the appropriate flow rates of the alkalinecarbonate and metal sulphate solutions.

After isolation the washed product was transferred to a vessel and driedin a preheated oven at 120° C. for three hours.

Product sample for analysis were ground using a ball mill (Retsch PM100). The milling parameters were set depending on the properties of theproduct.

Product sample for analysis was milled through a stainless steel, 200 mmdiameter, 106 μm sieve, using a sieve shaker (Retsch AS-200) Oversizematerial was returned to the stock dried sample to be reground, untilall material is <106 μm.

Example 2

Preparation method as for Example 1 but targeted to have a Mg:Fe molarratio of 2:1

The actual molecular formula found by analysis was:

[Mg₀₅₄Fe₀₃₆(OH)₂][(CO₃)_(y1)(SO₄)₀₀₃.0.20H₂O][Na₂SO₄]_(z)

Example 3

Preparation method as for Example 1 but targeted to have a Mg:Fe molarratio of 3:1.

Example 4

Preparation method as for Example 1 but targeted to have a Mg:Fe molarratio of 4:1

Example 5 & 6

[intentionally blank]

Example 7

Preparation method as for Example 1 but targeted to have a Mg:Fe molarratio of 2:1 and intended ageing (increase in crystallite size) byintroducing an additional method step immediately after precipitationwherein the reaction slurry is aged by heat treatment. The slurry isrefluxed for 4 hours by using a hot plate and a Liebig condenser toreflux the sample in a sealed flask. The sample was then immediatelyfiltered using a Buchner funnel under vacuum. The aged compound was thenisolated using the same method as described for Example 1

The actual molecular formula found by analysis was:

[Mg₀₆₆Fe₀₃₄(OH)₂][(CO₃)_(y1)(SO₄)₀₀₁.0.09H₂O][Na₂SO₄]_(z)

Example 8-24

Preparation method as for Example 2 but with a liquid ferric source of40.4 to 42.9 wt % ferric sulphate of water industry standard suitablefor human consumption conforms to BS EN 8902004). The method was thenvaried in that they were conducted at different precipitation pH,different excess of Na₂CO₃, and different reaction temperature i.e.either unaged (i.e. at relatively low reaction temperature 15, 30 or 65Celsius) or aged (at 90 Celsius) according to examples described below.Where the examples were unaged either the solutions were cooled (to 15Celsius) or no heat-treatment of reaction slurry occurred (at 30Celsius) or some gentle heating (at 65 Celsius); whereas when aged,heat-treatment of the reaction slurry occurred by using a sealed glassbeaker with condenser placed on a hotplate and reaction slurry heated at90° C. for 4 hours). Where a reaction temperature is not mentioned thereaction was conducted at the standard room temperature of approximately25-30 Celsius. The reaction slurry was cooled to 15 Celsius by placingthe metal beaker in an ice water bath; the temperature was monitored bya thermometer and controlled by the addition and removal of ice. Thereaction slurry was heated to 65 Celsius by placing the metal beaker ina thermostatically controlled water bath Grant W38, The temperature wasmonitored by a thermometer. The reaction slurry conducted at 30 Celsiusstarted at room temperature but gradually rose to a final temperature of30 Celsius after addition of the reagents. After the addition of thereagents the slurry was mixed for 30 minutes before filtration with theexception of example 21 which was mixed for 960 minutes.

The actual molecular formula determined by analysis, crystallite size,precipitation pH, slurry treatment, excess moles of Na₂CO₃ in recipe arelisted below for each example. Results of examples 8-24 are shown inTable 3 and FIG. 1.

Example  8[Mg_(0.2)Fe_(0.6)(OH)₂][(CO₃)_(0.16)(SO₄)_(0.0)•0.42H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 8.0; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃  9[Mg_(0.5)Fe_(0.5)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.39H₂O]•[Na₂SO₄]_(0.00)Crystallite size: >200 Å Precipitation pH = 9.8; reaction temperature is90 Celsius, 2.7 moles excess Na₂CO₃  9b[Mg_(0.5)Fe_(0.5)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.39H₂O]•[Na₂SO₄]_(0.00)Crystallite size: >200 Å Precipitation pH = 9.8; reaction temperature is90 Celsius; 4 moles excess Na₂CO₃ 10[Mg_(0.67)Fe_(0.38)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.01)•0.23H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 10.1; reactiontemperature is 65° C.; 2.7 moles excess Na₂CO₃ 11[Mg_(0.67)Fe_(0.33)(OH)₂][(CO3)_(0.14)(SO₄)_(0.01)•0.25H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.8; reactiontemperature is 65° C.; 2.7 moles excess Na₂CO₃ 12[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.01)•0.39H₂O][Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 11; reactiontemperature is 30 Celsius; 4 moles excess Na₂CO₃ 13[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.15)(SO₄)_(0.02)•0.39H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 10.5; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃ 14[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.23H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 10.3; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃ 15[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02)•0.73H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 10.5; reactiontemperature is 30 Celsius; 1 moles excess Na₂CO₃ 16[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02)•0.38H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 10.1; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃ 17[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.16)(SO₄)_(0.02)•0.37H₂O]•[Na₂SO₄]_(0.00)Crystallite size: <100 Å Precipitation pH = 9.8; reaction temperature is30 Celsius 2.7 moles excess Na₂CO₃ 18[Mg_(0.68)Fe_(0.34)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•0.65H₂O][Na₂SO₄]₀Crystallite size: not determined (nd) Precipitation pH = 9.8; reactiontemperature is 30 Celsius; 4 moles excess Na₂CO₃ 19[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.03)•0.38H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 11; reactiontemperature is 15° C.; 1 moles excess Na₂CO₃ 20[Mg_(0.64)Fe_(0.36)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•ndH₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.6; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃ 21[Mg_(0.64)Fe_(0.36)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.04)•0.56H₂O]•[Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.5; reactiontemperature is 30 Celsius; 2.7 moles excess Na₂CO₃ 22[Mg_(0.62)Fe_(0.38)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.04)•0.49H₂O][Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.5; reactiontemperature is 30 Celsius; 4 moles excess Na₂CO₃ 23[Mg_(0.64)Fe_(0.36)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.04)•0.52H₂O][Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.5; reactiontemperature is 30 Celsius, 1 moles excess Na₂CO₃ 24[Mg_(0.58)Fe_(0.42)(OH)₂][(CO₃)_(0.1)(SO₄)_(0.05)•0.43H₂O][Na₂SO₄]_(0.00)Crystallite size: not determined (nd) Precipitation pH = 9.5; reactiontemperature is 15° C.; 1 moles excess Na₂CO₃

Example 25-27

Preparation method and Mg:Fe ratio as for Example 2 with a ferric sourceof 40.4 to 42.9 wt % ferric sulphate of water industry standard suitablefor human consumption conforms to BS EN 890:2004 and with precipitationpH varied in accordance with Table 4 and filtered

Example The actual molecular formula found by analysis was: 25[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(y2) mH₂O]•[Na₂SO₄]_(0.00) 26[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(y2)•mH₂O][Na₂SO₄]_(z) 27[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02) mH₂O]•[Na₂SO₄]_(0.01)

Example 28

To make 163 kg of the mixed metal compound (dry basis) two startingsolutions were prepared designated solution A and solution B. To preparesolution A, 138 kg (dry basis) iron sulphate of 40.4 to 42.9 wt % ferricsulphate of water industry standard suitable for human consumptionconforms to BS EN 890:2004, 166 kg (dry basis) magnesium sulphate (addedas the hepta-hydrate) were dissolved in a total of 1034 kg of waterwhere this total water amount includes the water associated with theferric sulphate solution. To prepare solution B, 173 kg sodium hydroxideand 129 kg sodium carbonate were dissolved in 948 kg of water to providehomogenous solutions. The reaction vessel water heel was 840 kg. Thewater supplied to the heel was 30% of the total water supplied.

The reactant solution temperatures are adjusted to around 22° C. priorto addition. The reactant streams (solutions A and B) are thensimultaneously fed to the reaction vessel at a rate such as to maintaina reaction pH of 9.8. Cooling of the vessel contents is applied such asto maintain a temperature of 20-25° C. A heel of purified water isintroduced prior to the introduction of the reactant streams in order toenable agitation of the vessel in the initial reaction phase and to givea final slurry concentration of around 5.1 wt % compound

The vessel is agitated using a high turnover, low shear axial flowagitator operating at a power per unit volume of 0.1 kW/m³ and where thereactant solutions are delivered to an area of high turnover. Thereactor is baffled in order to promote good mixing.

The precipitate slurry is held in the reaction vessel (also referred toas hold time) for up to 12 hours and is transferred in aliquots to avertical filtering centrifuge for isolation and washing, using purifiedwater so as to provide maximum product rate. Washing is terminated toachieve a residual sodium content (expressed as Na₂O in the driedproduct) of less than 0.40 wt %.

The wet cake is discharged from the centrifuge and is dried in aspherical, agitated vacuum drier. Vacuum and shell temperature areadjusted to provide a product temperature in the dryer of approximately72° C. The rate of drying was 0.26 kg water/(kg dried product hr) aresidence time of 12 hours and a product rate per unit area of 4.6 kgproduct/(m²·hr).

The dried product is first coarse milled using a de-lumping mill to aparticle size distribution (Test Method 24) of typically 200 micron(D50) followed by final micronisation to a particle size of typically 5micron (D50).

Exam- ple The actual molecular formula found by analysis was: 28[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•0.20H₂O]•[Na₂SO₄]_(0.00)

Example 28b

Particle size distribution was measured in the reaction slurry after theaddition of the reagents and after a hold time of 4 hours and filtrationrate measured during the isolation step.

Example 28c Alternative Reaction Systems

CFD (Test Method 27) was applied to example 28 in order to derive amixing power per unit volume at the point of addition of the reactantstreams

The calculations were based on system having:

Slurry density: 1200 kg·m−3Slurry viscosity. 20 cP (0.02 Pa·s)Agitator Shaft speed: 100 rpmBaffling: Flat plates

The pattern of mixing is demonstrated via particle tracks from each ofthe two reactant stream inlets and shows that the streams remaineffectively segregated from each other before the fluid has dispersedwidely into the bulk Contours of concentration were also generated andconfirm that mixing into the bulk takes place very rapidly

To derive the requirements for the manufacture of mixed metal compoundsfor alternative mixing systems (e.g. static mixers), the findings forthe conventional low shear agitated system (described above) have beenapplied.

Alternative mixing systems such as static mixers, jet mixers, or dynamicin-line mixers and in particular a Kenics KM static mixer may besuitable to provide a volume in which the reaction can take place andsuitable to deliver the necessary mixing regime. For example the KenicsKM static mixer using a notional feed zone volume of 5×10⁻⁴ m³, toprovide a power to mass ratio (1.28 W/kg —equivalent to 1.54 kW/m³) andresidence time (1.25 sec). The length was fixed by the recommendedminimum length of 4 elements (hence L/D=6). The resulting diameter was100 mm and the flowrate 280 litre/min.

To summarise, for a conventionally agitated reaction systems a power perunit volume range (mixing intensity) of 0.03 to 0.5 kW/m3 has beenestablished as optimum. Using alternative mixing equipment, a power perunit volume range (mixing intensity) of 0.03 to 1.6 kW/m3 has beenestablished as optimum.

Example 29

As for example 28 but with a reaction pH of 10.3.

Example 30

As for example 28 but with a batch size of 7 kg using a single-aliquotfeed to the Neutsch filter instead of centrifuge such that the reactionmass is isolated and washed within a time period of no more than 16hours, a tray oven instead of a spherical drier and milled

The wet cake is discharged from the Neutsch filter and is dried in avacuum tray oven where the oven walls are heated to 120 to 130° C. andregular manual redistribution of the drying mass is carried out. Therate of drying was 0.38 kg water/(kg dried product hr) with a totaldrying time of 12 to 16 hours and a product rate per heated dryersurface area of 0.2 kg product/(m²·h).

The dried product is micronised using an impact mill to a particle sizeof typically 5 micron (D50, Test Method 24).

Example The actual molecular formula found by analysis was: 30[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.11)(SO₄)_(y2) 0.49H₂O]•[Na₂SO₄]_(z)

Example 31

As for example 30 but with a reaction pH of 10.3.

Exam- ple The actual molecular formula found by analysis was: 31[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.02)0.28H₂O]•[Na₂SO₄]_(0.0)

Example 32

As for example 28 but with a Vacuum Belt filter instead of centrifuge.Samples of wet cake discharged from the Vacuum Belt filter were dried inthe laboratory oven at 120° C. for three hours.

Product sample for analysis were ground using a ball mill to allow it topass through a 106 μm sieve.

Example 33

A reaction slurry was prepared according to the method of example 2 butwith a reaction pH of 9.6, a liquid ferric source (a solution 40.4 to42.9 wt % ferric sulphate of water industry standard suitable for humanconsumption conforms to BS EN 890:2004) and a nominal 400 cm³ batchsize. The reaction slurry was washed using Tangential Flow Filtration(Sartorius Slice 200 bench top system with 200 cm² filtration area, PESO0.1 micron membrane) operated in constant rate mode. The system wasflushed and filled with DI water prior to filtration, the permeate ratewas regulated to prevent filter blockage Filtration with wash wateraddition (diafiltration) was carried out to achieve a residual sodiumcontent (expressed as Na₂O in the dried product) of less than 0.40 wt %.The washed slurry was then concentrated using conventional vacuumfiltration and dried in a laboratory oven.

Example The actual molecular formula found by analysis was: 33[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(y2) mH₂O]•[Na₂SO₄]_(z)

Example 34

As for example 33 but with a reaction pH of 10.1

Example 35

As for example 33 but with a reaction pH of 10.3.

Example The actual molecular formula found by analysis was: 35[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(y2) mH₂O]•[Na₂SO₄]_(z)

Example 36

A reaction slurry was prepared for processing according to the method ofExample 28. However, 620 kg of reaction slurry were subsequentlyprocessed using Tangential Flow Filtration instead of centrifugation Areaction pH of 9.8 was used.

Prior to filtration, to reduce the risk of membrane blockage, thereaction slurry was circulated through a wet colloid mill in order toreduce the D50 particle size (Test Method 9) from 60 to 51 micron.

A Sartorius Sartoflow Beta filtration unit was used with eleven SartoconII membranes giving a total filtration area of 7.7 m2. The system wasflushed and filled with DI water prior to filtration, the permeate ratewas regulated to prevent filter blockage. A rotary lobe pump was used tocirculate slurry through the system at an inlet pressure of between 2and 3.5 bar and a typical retentate flow of 3400 I/h Filtration withwash water addition (diafiltration) was carried out until to achieve aresidual sodium content (expressed as Na₂O in the dried product) of lessthan 0.40 wt %.

A representative quantity of slurry was sampled and isolated and driedin accordance with the method of Example 1 but without additional cakewashing

Example 37

As for example 36 but with a reaction pH of 10.3. The particle size(D50, Test Method 9) was reduced by wet milling from 47 to 44 micron.

Example 38

As for example 28 but the method was then varied in that they wereconducted with slightly different drying conditions. The rate of dryingwas approximately 0.27 kg water/(kg dried product hr), a residence timeof 13 hours, a product rate per unit area of 1.4 kg product/(m²·hr), andthe maximum dryer temperature achieved is approximately 85° C.

Exam- ple The actual molecular formula found by analysis was: 38[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.03)•0.36H₂O]•[Na₂SO₄]_(0.00)

Example 39

As for example 28 but the method was then varied in that they wereconducted with different drying conditions. The rate of drying wasapproximately 0.38 kg water/(kg dried product hr), a residence time of 9hours and a product rate per unit area of 1.2 kg product/(m²·hr).

Exam- ple The actual molecular formula found by analysis was: 39[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02)•0.26H₂O]•[Na₂SO₄]_(0.00)

Example 40

As for example 30 but the method was then varied in that they wereconducted with different drying conditions. The rate of drying wasapproximately 0.21 kg water/(kg dried product·hr) a residence time of 18hours and a product rate per unit area of 0.1 kg product/(m²·hr)

Example 41

As for example 30 but the method was then varied in that they wereconducted with different drying conditions. The rate of drying wasapproximately 0.27 kg water/(kg dried product·hr) a residence time of 16hours and a product rate per unit area of 0.2 kg product/(m²·hr)

Example The actual molecular formula found by analysis was: 41[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02)•mH₂O]•[Na₂SO₄]_(0.00)

Example 42-47

As for example 28 but the method was then varied in that they wereconducted with different drying conditions as described in Table 7 whendried with a spherical, agitated vacuum drier (long residence dryer).

Ex- ample The actual molecular formula found by analysis was: 43[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.02)•0.53H₂O]•[Na₂SO₄]_(0.01)44[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)45[Mg_(0.67)Fe_(0.33)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)46[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•0.29H₂O]•[Na₂SO₄]_(0.00)47[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)

Example 48-49

As for example 28 (centrifugation) but the method was then varied inthat the filter-cake was dried using a short residence type drier(Spin-Flash Drier, manufacturer/model; Anhydro/SFD51) wherein the deltaT was 0.40 (Example 48) or a delta T of 0.66 (Example 49).

Conditions spray drier Rotor Product Example T_(in) (° C.) T_(out) (°C.) delta T speed (%) rate (kg/h) 48 250 150 0.40 90 8 49 350 120 0.6645 20

Delta T=(I _(in) −T _(out) /T _(in)

Exam- ple The actual molecular formula found by analysis was: 48[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.15)(SO₄)_(0.02)•0.19H₂O][Na₂SO₄]_(0.00)49[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.16H₂O][Na₂SO₄]_(0.00)

Example 50

As for example 36 (tangential flow filtration) but the method was thenvaried in that the slurry was dried using a short residence type drier(Spray Drier, manufacturer/model; Anhydro/CSD71) with a delta T of 0.69.

Conditions spray drier Example T_(in) (° C.) T_(out) (° C.) delta T Tipspeed (Hz) 50 350 110 0.40 208.3

Delta T=(T _(in) −T _(out))/T _(in)

Exam- ple The actual molecular formula found by analysis was: 50[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.37H₂O][Na₂SO₄]_(0.01)

Example 51-52

As for example 28 (centrifugation) but the method was then varied inthat the filter-cake was first diluted to provide a 10.1 wt % slurry andthen dried using a short residence type drier (Spray Drier,manufacturer/model, Anhydro/CSD71) wherein the delta T was 0.74 (Example51) or a delta T of 0.76 (Example 52).

Conditions spray drier Example T_(in) (° C.) T_(out) (° C.) delta T Tipspeed (Hz) 51 350 110 0.74 208.3 Hz 52 325 120 0.76 208.3 Hz

Exam- ple The actual molecular formula found by analysis was: 51[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.01)•0.34H₂O][Na₂SO₄]_(0.01)52[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.03)•0.38H₂O][Na₂SO₄]_(0.00)

Example 53-59

As for example 28 (centrifugation) but the method was then varied inthat instead of micronisation the dried product was only coarse-milledto 343 micron (μm) (D50) and hereafter separated into 6 differentparticle size fractions by sieving Six different sieves were used with asieve parameter size of respectively; base, 20 micron, 75 micron, 106micron, 180 micron, 355 micron. The sieve fractions were obtained byhand-sieving The 6 different sieve fractions (Example 53-58) obtained bythis method are described in Table 9.

Exam- ple The actual molecular formula found by analysis was: 53[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: >355 μm 54[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: 180-355 μm 55[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: 106-180 μm 56[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: 75-106 μm 57[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: <106 μm 58[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(y1)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)Sieve fraction: <20 μm 59[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•0.26H₂O]•[Na₂SO₄]_(0.00)micronised

Example 60

As for example 28 but the method was then varied in that they wereconducted with different drying conditions. The rate of drying wasapproximately 0.33 kg water/(kg dried product·hr), a residence time of9.8 hours and a product rate per unit area of 1.6 kg product/(m²·hr) andthe maximum dryer temperature achieved is approximately 76° C.

Example The actual molecular formula found by analysis was: 60[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.12)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)

Example 61

As for example 28 but the method was then varied in that they wereconducted with different drying conditions. The rate of drying wasapproximately 028 kg water/(kg dried product·hr), a residence time of10.3 hours and a product rate per unit area of 1.5 kg product/(m²·hr)and the product temperature achieved is approximately 64° C.

Example The actual molecular formula found by analysis was: 61[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.13)(SO₄)_(0.03)•mH₂O]•[Na₂SO₄]_(0.00)

Example 62-65

As for Example 2 but the method was then varied in that they wereconducted at different pH, different excess of Na₂CO₃ and differentferric source in accordance with Table 12, Furthermore, Example 62 wasprepared with aluminium sulphate in place of iron sulphate.

Two different ferric source designated A and B were used:

A: of GPR grade RectapurB: a more pure ferric source such as a solution 40.4 to 42.9 wt % ferricsulphate of water industry standard suitable for human consumptionconforms to BS EN 890:2004,

Exam- ple The actual molecular formula found by analysis was: 62[Mg_(0.79)Al_(0.21)(OH)₂][(CO₃)_(0.16)(SO₄)_(0.02)•mH₂O]•[Na₂SO₄]_(0.00)63[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.02)•0.22H₂O]•[Na₂SO₄]_(0.00)64[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(y1)(SO₄)_(0.02)•mH₂O]•[Na₂SO₄]_(0.00)65[Mg_(0.66)Fe_(0.34)(OH)₂][(CO₃)_(y1)(SO₄)_(0.01)•mH₂O]•[Na₂SO₄]_(0.00)

Example 66

As for example 28 but the method was then varied in that the filter-cakewas dried using a short residence type drier (Spin-Flash Drier,manufacturer/model; Anhydro/SFD51) wherein the delta T was 0.48.

Conditions spin flash drier Example T_(in) (° C.) T_(out) (° C.) delta TAtomiser speed, Hz 66 250 130 0.48 90

Delta T=(T _(in) −T _(out))/T _(in)

Example The actual molecular formula found by analysis was: 66[Mg_(0.65)Fe_(0.35)(OH)₂][(CO₃)_(0.14)(SO₄)_(0.03)•0.31H₂O]•[Na₂SO₄]₀

Methods

Test Method 1 XRF Analysis

XRF analysis of the product was performed by using a Philips PW2400Wavelength Dispersive XRF Spectrometer. The sample was fused with 50:50lithium tetra/metaborate (high purity) and presented to the instrumentas a glass bead AU reagents used were analytical grade or equivalentunless specified. AnalaR™ water, Lithium tetraborate 50% metaborate 50%flux (high purity grade ICPH Fluore-X 50). A muffle furnace capable of1025° C., extended tongs, hand tongs, Pt/5% Au casting tray and Pt/5%/Audish were used. 1.5 g (+/−0.0002 g) of sample and 7.5000 g (+/−0.0002 g)of tetra/metaborate was accurately weighed out into a Pt/5%/Au dish. Thetwo constituents were lightly mixed in the dish using a spatula, priorto placement in the furnace preset to 1025° C. for 12 minutes. The dishwas agitated at 6 minutes and 9 minutes to ensure homogeneity of thesample. Also at 9 minutes the casting tray was placed in the furnace toallow for temperature equilibration. After 12 minutes the molten samplewas poured into the casting tray, which was removed from the furnace andallowed to cool. The bead composition was determined using thespectrophotometer.

The XRF method was used to determine the Al, Fe, Mg, Na and totalsulphate content of the compound as well as the MII to MIII ratio

Test Method 2 X-Ray Diffraction (XRD) measurements

Data was collected for fine particulate samples from 2-70° 2θ on aPhilips automatic powder X-ray diffractometer using Copper K alpharadiation generated at 40 kV and 55 mA.

Powder X-ray diffraction (XRD) data were collected from 2-70 degrees 2theta on a Philips PW 1800 automatic powder X-ray diffractometer usingcopper K alpha radiation generated at 40 kV and 55 mA, a 0.02 degree 2theta step size with a 4 second per step count time. An automaticdivergence slit giving an irradiated sample area of 15×20 mm was used,together with a 0.3 mm receiving slit and a diffracted beammonochromator.

The approximate volume average crystallite size can be determined fromthe width, at half peak height, of the powder X-ray diffraction peak atabout 11.5 degrees 2 theta (the peak is typically in the range 8 to 15degrees 2 theta for hydrotalcite type materials) using the relationshipgiven in Table 1 which is derived using the Scherrer equation. Thecontribution to the peak width from instrument line broadening was 0.15degrees, determined by measuring the width of the peak at approximately21.4 degrees 2 theta of a sample of LaB₆ (NIST SRM 660) under the sameconditions.

TABLE 1 XRD Peak width conversion to crystallite size using the Scherrerequation Peak width D - FWHM B B (measured) - b Calculated (measured)(instrument) crystallite (°2Θ) (°2Θ) size (Å) 0.46 0.31 258 0.47 0.32250 0.48 0.33 242 0.49 0.34 235 0.50 0.35 228 0.51 0.36 222 0.52 0.37216 0.53 0.38 210 0.54 0.39 205 0.55 0.40 200 0.56 0.41 195 0.57 0.42190 0.58 0.43 186 0.59 0.44 181 0.60 0.45 177 0.61 0.46 174 0.62 0.47170 0.63 0.48 166 0.64 0.49 163 0.65 0.50 160 0.66 0.51 157 0.67 0.52154 0.68 0.53 151 0.69 0.54 148 0.70 0.55 145 0.71 0.56 143 0.72 0.57140 0.73 0.58 138 0.74 0.59 135 0.75 0.60 133 0.76 0.61 131 0.77 0.62129 0.78 0.63 127 0.79 0.64 125 0.80 0.65 123 0.81 0.66 121 0.82 0.67119 0.83 0.68 117 0.84 0.69 116 0.85 0.70 114 0.86 0.71 112 0.87 0.72111 0.88 0.73 109 0.89 0.74 108 0.90 0.75 106 0.91 0.76 105 0.92 0.77104 0.93 0.78 102 0.94 0.79 101 0.95 0.80 100 0.96 0.81 99 0.97 0.82 970.98 0.83 96 0.99 0.84 95 1.00 0.85 94 1.01 0.86 93 1.02 0.87 92 1.030.88 91 1.04 0.89 90 1.05 0.90 89 1.06 0.91 88 1.07 0.92 87 1.08 0.93 861.09 0.94 85 1.10 0.95 84 1.11 0.96 83 1.12 0.97 82 1.13 0.98 81 1.140.99 81 1.15 1.00 80 1.16 1.01 79 1.17 1.02 78 1.18 1.03 78 1.19 1.04 771.20 1.05 76 1.21 1.06 75 1.22 1.07 75 1.23 1.08 74 1.24 1.09 73 1.251.10 73 1.26 1.11 72 1.27 1.12 71 1.28 1.13 71 1.29 1.14 70 1.30 1.15 691.31 1.16 69

The values in Table 1 were calculated using the Scherrer equation:

D=K*λ/β*cos Θ  Equation 1

Where:

-   -   D=crystallite size (A)    -   K=shape factor    -   A=wavelength of radiation used (in A)    -   β=peak width measured as FWHM (full width at half maximum        height) and corrected for instrument line broadening (expressed        in radians)    -   Θ=the diffraction angle (half of peak position 2Θ, measured in        radians)

Shape Factor

This is a factor for the shape of the particle, typically between0.8-1.0, a value of 0.9 is used.

Wavelength of Radiation

This is the wavelength of the radiation used For copper K alpharadiation the value used is 1.54056 Å.

Peak Width

The width of a peak is the sum of two sets of factors: instrumental andsample.

The instrumental factors are typically measured by measuring the peakwidth of a highly crystalline sample (very narrow peaks). Since a highlycrystalline sample of the same material is not available, LaB₆ has beenused. For the current measurements an instrument value of 0.15 degreeshas been used.

Thus for the most accurate measure of crystallite size using theScherrer equation, the peak width due to instrumental factors should besubtracted from the measured peak width i.e.:

β=B _((measured)) −b _((instrumental))

The peak width is then expressed in radians in the Scherrer equation.

The peak width (as FWHM) has been measured by fitting of a parabola oranother suitable method to the peak after subtraction of a suitablebackground.

Peak Position

A value of 11.5° 2Θ has been used giving a diffraction angle of 5.75°.Corresponding to 0.100 radians.

Test Method 3 Phosphate Binding Capacity and Mg Release

Phosphate buffer (pH=4) was prepared by weighing 5.520 g (+/−0.001 g) ofsodium di-hydrogen phosphate followed by addition of AnalaR™ water andtransferring to a 1 Itr volumetric flask

To the 1 litre volumetric flask was then added 1M HCl drop-wise toadjust the pH to pH 4 (+/−0.1) mixing between additions. The volume wasthen accurately made up to 1 Itr using AnalaR™ water and mixedthoroughly.

0.5 g (+/−0.005 g) of each sample was added to a volumetric flask (50ml) containing 40 mM phosphate buffer solution (12.5 ml) at 37.5° C. ina Grant OLS 200 Orbital shaker. All samples were prepared in duplicate.The vessels were agitated in the orbital shaker for 30 minutes. Thesolution was then filtered using a 0.45 μm syringe filter. 2.5 cm³aliquots of supernatant were pipetted of the supernatant and transferredinto a fresh blood collection tubes. 7.5 cm³ of AnalaR™ water werepipetted to each 2.5 cm³ aliquot and the screw cap fitted and mixedthoroughly. The solutions were then analysed on a calibrated ICP-OES.

The phosphate binding capacity was determined by:

Phosphate binding(mmol/g)=S_(P)(mmol/l)−T _(P)(mmol/l)/W(g/l)

where:

-   -   T_(P)=Analyte value for phosphate in the phosphate solution        after reaction with phosphate binder=solution P (mg/l)*4/30.97.        S_(P)=Analyte value for phosphate in the phosphate solution        before reaction with phosphate binder.        W=concentration binder (g/l) used in test method (i.e 0.4 g/10        cm³=40 g/l)

Magnesium release was determined by:

Magnesium release(mmol/g)=T _(Mg)(mmol/l)−S _(Mg)(mmol/l)/W g/l)

where:

-   -   T_(Mg)=Analyte value for magnesium in the phosphate solution        after reaction with phosphate binder=solution Mg(mg/l)*4/24.31.    -   S_(Mg)=Analyte value for magnesium in the phosphate solution        before reaction with phosphate binder.        Fe release was not reported as the amount of iron released from        the compound was too small and below detection limit.

Test Method 4 Phosphate Binding and Magnesium Release in Food Slurry

MCT peptide2+, food supplement (SHS International) was mixed to form aslurry of 20% (w/v) in 001M HCl. Separate aliquots of 0.05 g drycompound were mixed with 5 cm³ of the food slurry and constantlyagitated for 30 minutes at room temperature. A 3 cm³ aliquot was removedand centrifuged at 4000 rpm for 10 minutes, and the phosphate andmagnesium in solution were measured.

Test Method 5 Sulphate Determination Total Sulphate in the Compound

Sulphite (SO3) is measured in the compound by XRF measurement (TestMethod 1) and expressed as total sulphate (SO4) according to:

Total SO4(wt %)=(SO3)×96/80.

Total SO4(mole)=total SO4(wt %)/molecular weight SO4

Sodium Sulphate (soluble form of sulphate present in the compound)

Na2O is measured in the compound by XRF measurement (Test Method 1).

It is assumed that the Na2O is associated with the more soluble form ofSO4 in the form of Na2SO4 present in the compound.

Consequently, the number of mole Na2O is assumed equal to that ofsoluble form of sulphate and is therefore calculated as:

soluble SO4(mole)=Na2O(mole)=wt % Na2O/molecular weight Na2O

Interlayer sulphate (insoluble form of sulphate present in the compoundalso referred to as bound sulphate)

The interlayer sulphate is calculated according to

interlayer SO4(mole)=total SO4(mole)−soluble SO4(mole)

interlayer SO4(wt %)=interlayer SO4(mole)×molecular weight SO4

Test Method 6 Carbon Content Analysis by the Leco Method

This method was used to determine the levels of carbon content(indicative of the presence of the carbonate anion present in the mixedmetal compound)

A sample of known mass is combusted at around 1350° C. in a furnace in apure oxygen atmosphere. Any carbon in the sample is converted to CO₂which is passed through a moisture trap before being measured by aninfra-red detector. By comparing against a standard of knownconcentration, the carbon content of the sample can be found. A LecoSC-144DR carbon and Sulphur Analyser, with oxygen supply, ceramiccombustion boats, boat lance and tongs was used 0.2 g (+/−0.01 g) ofsample was weighed into a combustion boat. The boat was then placed intothe Leco furnace and the carbon content analysed. The analysis wasperformed in duplicate

The % C was determined by:

% C(sample)=(% C₁+% C₂)/2

Where C₁ and C₂ are individual carbon results

The results of the carbon content measurements are seen in Table 3 andFIG. 1 and were expressed as % CO₂=% C x 44/12

Test Method 7 Wash Time

Wash time was measured in minutes rounded to the nearest minute, it wasthe time it took for one wash (i.e. one wash volume of water) to bedrawn through the filter. The wet cake was not allowed to dry or crackduring this period. The time was measured using a stop clock.

Test Method 8 Filtration Time (Lab scale)

Filtration time was measured in minutes rounded to the nearest minute,it was the time taken for the slurry to be drawn through the filter, butthe resulting wet cake was not allowed to dry. The time was measuredusing a stop clock.

Test Method 9 Particle Size Distribution (PSD) by Lasentech

In process particle size distribution in the slurry was measured using aLasentech probe The d50 average particle size, is obtained as part ofthis analytical technique

Test Method 10 Filtration Rate (ml/min)

Defined as the quantity of filtrate obtained in a given time.

Test Method 11 Filtration Rate (kg dry product/m²·h)

Filtration Rate (kg dry product/m²·h) is defined as the mass of wetcake, expressed as dried compound, isolated, washed, dewatered anddischarged per hour, divided by the area of filter used.

Test Method 12 Moisture Content

The moisture content of mixed metal compound is determined from the lossof weight (LOD) following drying at 105′C for four hours at ambientpressure in a laboratory oven

Test Method 13 [Intentionally Left Blank] Test Method 14 Surface Areaand Pore Volume (Nitrogen Method—N₂)

Surface area and pore volume measurements were obtained using nitrogengas adsorption over a range of relative pressures using a MicromeriticsTristar ASAP 3000. The samples were outgassed under vacuum for 4 hoursat 105° C. before the commencement of measurements. Typically a vacuumof <70 mTorr was obtained after outgassing.

Surface areas were calculated by the application of Brunauer, Emmett andTeller (BET) theory using nitrogen adsorption data obtained in therelative pressure range of 0.08 to 0.20 P/Po.

Pore volume was obtained from the desorption loop of the nitrogenadsorption isotherm, using the volume of gas adsorbed at a relativepressure (P/Po) of 0.98. The quantity of gas adsorbed at 0.98 relativepressure (in cc/g at STP) is converted to a liquid equivalent volume bymultiplying by the density conversion factor of 0.0015468. This givesthe reported pore volume FIGURE in cm³/g.

P=partial vapour pressure of nitrogen in equilibrium with the sample at77KPo=saturated pressure of nitrogen gas.Test Method 15 Pore Volume (water method)

Water Pore Volume Aim

To fill internal pores of a sample (in powder form) with water suchthat, when all the pores are filled, the surface tension of the liquidcauses the majority of the sample to form an aggregate which adheres toa glass jar on inversion of the jar. Equipment

(1) Wide neck (30 mm) clear glass 120 cm³ powder jar with screw cap.Dimensions: Height 97 mm. Outer Diameter 50 mm. (Fisher part numberBTF-600-080)(2) 10 cm³ Grade A burette(3) Deionised water(4) Rubber bung 74 mm diameter top tapered to 67 mm. Overall height 49mm(5) Calibrated 4 decimal place balance Procedure(1) a 5.00 g (±0.01) sample in the glass jar, add a 1 cm³ aliquot ofwater(2) After this addition vigorously knock the bottom end of the sealedjar against the rubber bung 4 times.(3) Using a sharp swing of the arm, flick the jar with the wrist toinvert the jar and check the sample:a. If the sample agglomerates and the majority (>50%) of the sampleadheres to the jar this is the end point (go to results section below).If free water is observed with the sample, the end point has beenexceeded and the test should be discarded and started again with a newsample.b. If the sample dislodges from the jar (even if agglomeration isevident), add a further 0.1 cm³ of water and repeat steps (2) to (3)above until the end point is reached(3a)).

Results

The water pore volume is calculated as follows.—

Water Pore Volume (cm³/g)=Volume of water added (cm³)/Sample Weight (g)

Test Method 16 Total Water Added/Kg API-Granulation Point

This is the amount of water added to a dry mixture of 80 wt % mixedmetal compound and 20 wt % excipients in order to form granulates (i.e.until a granulation point is reached).

Test Method 17 Tablet Volume

The tablet volume is calculated from the dimensions of the tablet usinga computer design package (iHolland Ltd).

Test Method 18 Rate of drying

For the calculation of rate of drying (kg water/(kg dried product·hr))mass of water removed during drying per unit time was divided by themass of dry product produced. The time used to calculate the rate ofdrying is the dryer residence time defined in Test Method 19.

Test Method 19 Dryer Residence Time

For long residence dryers, the residence time is the time during whichwater is removed from the material being dried.

For short residence dryers such as spray drying, the residence time iscalculated as follows

The internal volume of the dryer is first determined. The residence timeof the air or gas fed to the dryer is then calculated by dividing theinterval volume by the air or gas flow rate. It is assumed, since asignificant build up of solids does not occur within the dryer, that theaverage particle residence time is approximately equal to the air or gasresidence time.

Test Method 20 Product Rate Per Unit Area

The Product rate per unit area kg product/(m²·hr) can be calculated bydividing the mass of dry product produced per unit time with the surfacearea used for heating.

Test Method 21 Delta T

Delta temperature is defined for short residence drying processes as (T_(in) −T _(out))/T _(in)

where

-   -   T_(in) is inlet gas temperature, ° C.    -   T_(out) is the outlet gas temperature or product temperature,        ° C. (assuming gas and product are at the same temperature)

Test Method 22 Tapped Bulk Density

Tapped Bulk Density was determined using a Copley JV1000 Auto tapper.The measurement was made by the addition of the product (50.0 g, +/−5.0g) into a clean measuring cylinder (dedicated for the apparatus). Theexact weight was noted. The initial volume was noted. The cylinder wasthen placed on the auto tapper and the machine was set for 3750 taps byentering the number of taps required and then pressing start. The volumeof the cylinder was taken again when the total number of taps wascompleted (end volume). The tapped bulk density was calculated asfollows,

Tapped Bulk Density (g/ml)=weight (g)/end volume (ml)

Test Method 23 Flowability Carr Index

The Carr index was calculated using the following formula and the dataavailable from the Tapped Bulk Density test,

Carr Index (%)=100*((initial volume (ml)−end volume (ml))/initial volume(ml))

A result greater than 25% indicates poor flow ability and less than 15%indicates good flow ability.

Test Method 24 Average Particle Size Distribution (d50 PSD) of Powders

The particle size was determined using a Mastersizer ‘S’ fitted with a300Rf lens and a DIF 2012 dispersion unit. The data was interpreted andanalysed using Malvern Mastersizer software. The Malvern was connectedto process water supply. The following program parameters were used, 80%pump speed, 80% stirrer speed, 50% ultrasonic and 3 minute residencetime. The background level was checked to be below 100 units. Whenprompted by the program the sample was added in portions to reachbetween 15%-25% obscuration. The analysis commenced automatically. Theresidual was checked to be less than 1%. The sample was analysed induplicate. The results were calculated using the software by taking the% volume under the particle sizes between 1.85 and 184 microns. This wasexpressed as percentile results with the Average Particle Size (D50,50^(th) percentile), 90^(th) Percentile (D90) and 10^(th) Percentile(D10)

Test Method 25 Metal Analysis of Al, Cr, Pb

Samples were acidified, diluted and the specified metals analysed using1CP-MS. Samples were analysed in duplicate.

Test Method 26 Total Heavy Metal Content

The metals were determined by acidifying the samples first followed byanalysis using ICP-MS. Total heavy metal content (ppm) was thencalculated by summating the following metals.As(ppm)+Cd(ppm)+Pb(ppm)+Hg(ppm)+Sb(ppm)+Mo(ppm)+Cu(ppm)

Test Method 27—Power per Unit Volume

Computational Fluid Dynamics (CFD) software application was used tosimulate fluid flow within the reaction vessel to establish mixingrequirements in mixing equipment.

Results and Discussion

We have encountered critical problems with the larger scale process ofmanufacture (defined as being from the reaction to drying stages) whentrying to prevent increase in crystallite size. This is described inmore detail below

Phosphate Binding

For, high daily and repeated long-term (chronic) dosages required forkidney patients total daily pill count requires a low tablet burden dueto restricted fluid intake. Consequently, high dosage of drug substance(mixed metal compound) of up to 80 wt % is required in final product(i.e. tablet) whilst maintaining good therapeutic activity (such asphosphate binding) and storage stability. We have found that the finalproduct is therefore very sensitive to an array of opposing chemical andphysical properties of the mixed metal compound such as composition(Mg:Fe ratio, sulphate), crystallite size, morphological properties(surface area, particle size, pore volume) of the mixed metal compounds.This is unlike normal requirements imposed on pharmaceuticals whichtypically contain more soluble, organic type drug substances at lowerconcentrations which are less dependent on a particular morphology.

Variants of the Mg:Fe hydrotalcite structure that had different Mg:Femolar ratios of 2:1, 3:1 and 4:1 were compared for phosphate bindingperformance and magnesium release (Table 2). The release of themagnesium, associated with the pharmaceutical use of mixed metalcompounds can be reduced by selecting a suitable Mg:Fe molar ratio. Datashowed that material with a ratio of 21 had the highest phosphatebinding per mole of magnesium released in a phosphate binding test inthe presence of a meal slurry. The data also shows that a Mg:Fe molarratio of 2:1 does not have the presence of any other non-hydrotalcitephases. In addition, we have found that unaged mixed metal compounds ofcrystallite size less than 200 angstrom (Å) give higher phosphatebinding than those of aged compounds which typically have a crystallitesize well above 200 Å.

TABLE 2 Selection of preferred Mg:Fe Molar ratio and Crystallite SizePhosphate bound Additional Non- Crystallite Phosphate per mmol/l MgHydrotalcite Mg:Fe Size Binding released Phases Example Ratio Method 2Method 3 Method 4 (food slurry) Method 2 Number Method 1 Angstrom (Å)mmol/g API (%) XRD 1 1.0 95 0.77 yes 2 2.0 69 0.73 23.00 no 3 3.0 <1007.70 no 4 4.0 <100 0.73 5.70 no 7 2.0 258 0.45 no

However, we have found that if processed incorrectly the mixed metalcompounds crystallite size will continue to grow in size and aredifficult to filter, particularly at large scale this presentssignificant problems. We have discovered a novel process for control ofdifferent production steps (from reaction to drying) such as to preventgrowth of the crystallite size above 200 Å in order to maintain thephosphate binding activity without significantly hindering the processof isolation, washing and drying of the compound. This was achieved bycareful selection and control of specific process conditions. Ourapproach is described in more detail by the following examples.

Precipitation

We have found that the advantages of the mixed metal compound of Mg:Femolar ratio of approx 2.1 such as good phosphate binding are not onlydetermined by crystallite size but also preferably by low levels ofinterlayer sulphate and the method of manufacture (Table 3 and FIG. 1).Furthermore, across the pH range considered, filtration is difficult dueto the typical clay-like structure of the material.

When preparing the mixed metal compound with the carbonate anion thepresence of a second anion-type may be possible. The presence of onlyone anion-type may be considered more desirable than a mixture ofanions. Surprisingly, we discovered that it is not necessarily optimalto have no sulphate but that a small amount of sulphate should exist asinterlayer (bound) sulphate in order to increase filtration rates of theclay-like structure whereas the sulphate in the form of soluble saltssuch as Na₂SO₄ should be removed. We found that most of the solubleNa₂SO₄ salt can be readily removed by washing whereas the interlayersulphate is less soluble and its levels are primarily controlled by theamount of excess Na₂CO₃ in the recipe, reaction pH and extent of ageingin the reaction slurry (i.e. temperature of reaction slurry). Forexample, we have found that the interlayer sulphate decreases when:reaction temperature of slurry increases, the excess Na₂CO₃ increases,the pH increases.

Optionally, if the interlayer sulphate needs to be reduced further toachieve an even higher purity (i.e. less than 1.0 wt % interlayersulphate) and initial isolation and washing rates are not to be reducedit may be possible to wash the filter cake again but this time with asolution of Na₂CO₃ (preferably up to 1 M concentration) followed bywashing with water. This process may reduce or remove the remaininginterlayer sulphate without necessarily reducing filtration rates orphosphate binding. However, it is preferred if most of the interlayersulphate is removed during the reaction stage instead of requiring theneed for washing with carbonate. Additional process steps may decreaseyield as well as encouraging crystallite size growth.

Therefore in another aspect of the invention the compound is firstwashed with water to remove soluble SO₄ and sodium, followed by a washwith a Na₂CO₃ solution to remove the interlayer sulphate, followed by afinal wash with water to remove any remaining soluble ions. Preferablythe compound is slurried with some Na₂CO₃ solution for up to 1 hour toenable exchange of the interlayer sulphate for the carbonate. It isbelieved that washing with excess Na₂CO₃ would encourage removal of anyremaining sulphate from the interlayer region. In this aspect after theexchange of the interlayer sulphate for the carbonate there may beprovided an Al-free mixed metal compound with less than 1 wt %interlayer sulphate (preferably less than 0.5 wt %) and less than 0.5 wt% soluble sulphate.

Where product is not washed with Na₂CO₃ solution we have also found thatphosphate binding varies as a function of sulphate level, for example,an optimum interlayer sulphate level exists of between 1.8 to 5% wt,wherein good phosphate binding and filtration is maintained. Phosphatebinding decreases below 1.8% wt. Above 5% wt interlayer SO₄ becomes morevariable and the SO₄ level is too high to be acceptable and wash andfiltration time increases. Best results were obtained between 2.5 and 5wt % interlayer sulphate.

TABLE 3 Effect and control of interlayer sulphate on wash time andphosphate binding

Area highlighted is preferred range

Separation

The features of the Al-free mixed metal compounds resulting from theirclay-like structure, replacing Al with Fe and their unaged form presentlimitations when manufactured on a commercial scale. Limitations such asdifficult filtration and material hardness have to be resolved whilst atthe same time maintaining a process at scale and a mixed metal compoundswith good phosphate binding, storage stability and not negativelyaffecting the downstream manufacturing processes used to produce thefinal formulated pharmaceutical product containing the mixed metalcompound.

During scale-up we found that it was difficult to prepare this materialwhen using traditional filtration techniques such as a belt filter,Neutsche pressure filter. Even a centrifugation method did not workeffectively at this large scale.

We solved this problem by selecting specific ranges from one or more ofthe following: (i) selection of range of interlayer sulphate (from 1.8to 5 wt %) by control of Na₂CO₃ and pH (ii) selection of a preferred psdof reaction slurry (D50 >40 microns, preferably greater than 70 microns)and moisture content of reaction slurry (more than 90 wt %) and filtercake (less than 80 wt %) (iii) selection of a specific agitation regime(a power per unit volume of 0.03 to 1.6 kW/m³), (iv) selection of apreferred filtration method and its operation (centrifuge). In a highlypreferred aspect we selected each of the following: (i) selection ofrange of interlayer sulphate (from 2 to 5 wt %) by control of Na₂CO₃ andpH (ii) selection of a preferred psd of reaction slurry (D50 >40microns, preferably greater than 70 microns) and moisture content ofreaction slurry (more than 90 wt %) and filter cake (less than 80 wt %)(iii) selection of a specific agitation regime (a power per unit volumeof 0.03 to 1.6 kW/m³), (iv) selection of a preferred filtration method(centrifuge).

(i) Interlayer Sulphate

A high filtration rate and a low wash time are advantageous when seekingto manufacture the MgFe mixed metal compounds on a commercial scale andto prevent crystallite growth. However, mixed metal compounds consistingof low interlayer sulphate levels (less than 1.8 wt %) are moredifficult to filter and wash whereas if too high in sulphate (above 5 wt%) then washtime increases again (Table 3 and FIG. 1). We found thatinterlayer sulphate levels can be maintained between 2-5 wt % bycontrolling the temperature of the reaction slurry, pH during thereaction and a Na₂CO₃ (XS) excess range of either one of the followingcombinations shown below

When the slurry is maintained to a temperature between 15 and 30° C.wherein the Na₂CO₃ is provided at an excess than is required to completethe reaction and a pH at either:

(i) 9.5<pH≦11 and 0≦Na₂CO₃≦1 moles(ii) 9.5≦pH≦10.5 and 1<Na₂CO₃≦2 moles(iii) 9.5≦pH≦10.1 and 1<Na₂CO₃≦2.7 moles(iv) 9.5≦pH<10 and 1<Na₂CO₃≦4 moles(v) 9.5≦pH<9.8 and 1<Na₂CO₃≦5 moles

When the slurry is maintained to a temperature from 30 to 60° C. whereinthe Na₂CO₃ is provided at an excess than is required to complete thereaction and a pH at either:

(i) 9.5<pH<11 and 0<Na₂CO₃<2(ii) 9.5<pH<10.5 and 0<Na₂CO₃<2.7 moles(iii) 9.5<pH<10 and 0<Na₂CO₃<4 moles

Excess Na₂CO₃ (XS) is defined as excess than is required to complete thereaction of

4MgSO₄+Fe₂(SO₄)₃+12NaOH(XS+1)Na₂CO₃->Mg₄Fe₂(OH)₁₂.CO₃.nH₂O+7Na₂SO₄+(XS)Na₂CO₃

For mixed metal compounds, maintaining the target metal molar ratio(Mg:Fe) at approx 2 (1.8 to 2.2, preferably 1.7 to 2.1) during thereaction whilst controlling the interlayer sulphate is difficult as bothare opposingly affected by the way the material is processed.Furthermore, we found that correct stoichiometry is not only determinedby the correct ratios of the starting materials but also by pH for thereaction. For example, when the pH is too low (pH below 9.5) incompleteprecipitation of magnesium may occur whereby Mg:Fe molar ratio fallswell below the target value of 2 and is also not free ofnon-hydrotalcite crystalline phases. It is therefore preferred tomaintain the pH between 9.5 and 11 and preferably between an evennarrower pH range of 9.5-10 and more preferably at 9.8 to deliver theoptimum magnesium:iron ratio (1.8 to 2.2, preferably 1.7 to 2.1) whilstmaintaining good filtration rates during manufacture at scale, maintaingood phosphate binding and prevent crystal growth by control of particlesize distribution and interlayer sulphate.

The total amount of anion (C_(calc)) predicted for a mixed metalcompound if it were of an ideal hydrotalcite type phase of a M²⁺:M³⁺molar ratio of 2:1 can be calculated by the following formula:C_(calc)=(M³⁺/(M²⁺+M³⁺))/n wherein n is the charge of the anion. Forexample, a M²⁺:M³⁺ molar ratio of 2:1 and an assumed anion charge n=2(i.e. as for CO₃ ²⁻ or SO₄ ²⁻) would result in a predicted value for(C_(calc)) of 0.17. The experimental value for C_(exp) can be determinedfrom the sum of the amount (mole equivalent) of sulphate and carbonateanion. The Δ is defined as the difference between the C calculated and Cexperimental wherein a lower Δ value indicates a more pure hydrotalcitephase. The smallest Δ value is observed when precipitating above pH 9.5.

The data of Table 3 (shown in FIG. 1) and the description of examples8-24 in the example section shows that the best overall quality (i.e.good phosphate binding, high filtration rates, low wash times, a molarratio of approximately 2.0, no non-hydrotalcite crystalline phases and asmall Δ) are obtained for those samples wherein the interlayer sulphatelevels are between 2 and 5 wt %, and preferably a sulphate to carbonatemolar ratio of between 0.14 to 0.26. The total amount of anion (sulphateand carbonate) is preferably from 0.15 to 0.20 more preferably is of0.19 mole equivalent.

In order to control interlayer sulphate below 3%, the Na₂CO₃ had to beof more than 2 mole excess. To maintain the interlayer sulphate above 2wt % the precipitation pH has to be less than 10 and of 2.7 moles excessNa₂CO₃ or less

Sodium carbonate not only provides the carbonate for the anion-exchangesites, but also acts as a pH buffer which assists pH control duringprecipitation. The ability to maintain an accurate precipitation pH isconsiderably increased when Na₂CO₃ is present and for that reason anexcess of Na₂CO₃ of more than 2 is preferred. However, we found that anexcess Na₂CO₃ of 4 or above is less preferred because this could resultin an increased risk of incomplete dissolution of Na₂CO₃ in the reactantsolution at the preferred reaction temperatures (of less than 25° C.)when preparing unaged mixed metal compounds

For example, during dissolution of the sodium hydroxide and sodiumcarbonate in the feed-solutions, the solution temperature may rise to65° C. and we found that an excess in Na₂CO₃ of 4 or more does dissolve;however, cooling and/or pressurisation was required during dissolutionto limit evaporation and to lower the temperature to the same value asthat required for the reaction to prevent ageing. When the Na₂CO₃solution (of more than 4 mole excess) is cooled from 65 to 25° C.partial precipitation of the Na₂CO₃ occurs.

It was therefore preferred to maintain the Na₂CO₃ at 4 mole excess orless. We found that it was possible to lower the excess Na₂CO₃ from 4 to2.7 mole without affecting pH control.

To summarise, the data of Table 3 suggest that when outside a range ofto 5 wt % interlayer sulphate, phosphate binding either decreases and/orthe Mg:Fe molar ratio of 2.0 is not maintained and/or separation of theslurry is more difficult to achieve A Mg:Fe molar ratio of 2.0 wastargeted such as to obtain the highest phosphate binding per mole ofmagnesium released A preferred range of between 1.8 to 5 wt % interlayersulphate was achieved by selection of pH and Na₂CO₃ excess within anarrow range.

(ii) Reaction slurry psd and filter cake moisture content

Particle Size Distribution (PSD)—The particle size distribution is animportant material parameter which influences the filtration time of thereaction precipitate slurry. In the laboratory with similar reactantconcentration, reactant addition rate, reaction temperature and pH andwater heel volume, differing agitation configurations produced differentPSDs. Thus the PSD of the reaction precipitate is strongly influenced bythe agitation regime, the vessel configuration, and the mode of reactantaddition. We have identified the agitation conditions at commercialscale to enable optimum filtration and washing conditions whilstensuring that the final product is essentially unchanged from that atlow tones per annum scale.

Without being bound by theory it is postulated that high pH/sub-optimalmixing can result in a small particle size which can block up the filtercloth, reduce the filtration rate through the cake and limit theultimate solids content of the filter cake. We found that there is asignificant increase in filtration time when reaction slurry psd (d50)is reduced to less than 70 microns. Investigations (data shown in Table4) demonstrated that control of particle size above approximately 70microns is preferable in maintaining a high filtration rate suitable foruse of separation methods on a commercial scale such as centrifuge,Neutsch and belt filters. In addition, we found that unwanted crystalgrowth (ageing) can be minimised if filtration time is kept at aminimum. We also found that a reduction in particle size to less than 70microns leads to an increase in moisture content of the filter cake tomore than 80 wt %. This filter cake is stickier and is therefore moredifficult to remove from the filtration equipment and will tend to holdup in mechanical devices or containers during handling. A preferredmoisture content of the filter cake is therefore less than 80 wt %.Consequently, separating the mixed metal compound from reaction slurryof more than 90 wt % moisture content is also preferred.

There is therefore a preferred combination of both a filter cake ofmoisture content (less than 80 wt %) and a PSD (of more than 70 microns)to enable manufacture on a larger scale of compositions free ofaluminium.

(iii) Agitation Regime

The results described herein demonstrate that the preferred PSD ofreaction slurry are obtainable when maintaining the reaction pH betweenpH 9.5-11 (preferably at pH 9.5 to 10, more preferably 9.8). In general,the teachings of WO99/15189 would not enable separation of the compoundon a commercial scale. Furthermore, we found that the method ofagitation (power per unit volume of 0.03 to 1.6 kW/m³) duringprecipitation is preferred. Slow stirring (i.e. sufficient to maintainthe solution homogeneous) was then maintained during the hold time. Wefound that filtration time increased significantly when the slurry isstirred for a prolonged period during the hold time. For example, wefound that a hold time of more than 30 minutes but less than 12 hours ispreferred and the slurry during hold time should be agitated gently. Theslurry hold time is defined as the time period between when the additionof Solutions A and B ceases (reaction phase ends) and the last aliquotof slurry is added to the filtration equipment. At pilot plant and largecommercial scale where centrifuges are used, the slurry hold time istypically up to 12 hours since multiple aliquots of reaction mass areisolated, washed, dewatered and discharged as wet cake.

The specific reaction agitation configuration to maintain low shearconditions whilst at the same time enabling sufficient mixing were alsofound to be useful in obtaining a preferred psd of more than 70 microns(when measured at the end of hold time). The specific power input has tobe controlled such as to avoid a rate which is too low but not at a ratewhich breaks the particles down into very fine particles of psd lessthan 70 microns Evaporation of water from the reaction slurry and ageingof crystallites was prevented by maintaining the reaction temperaturebelow 30 Celsius and typically was not less than 15 Celsius to avoidunacceptable reduction in reactant feed stream solubility.

TABLE 4 Effect of slurry Particle Size Distribution (PSD) onfilterability PSD Filtration Filtration Mg:Fe reaction Time Rate Moleslurry d50 Slurry (Lab (Lab Ratio (Lasentec) Time of psd hold scale)Scale) Example Precipitation Filtration Method Method 9 measurement timeMethod 8 Method 10 Number pH type 1 microns hrs hrs seconds ml/min 259.6 Lab 1.9 81 2 2 37 n/a Filter 26 10.1 Lab 1.9 69 4 4 177 n/a Filter27 10.3 Lab 2.1 60 4 4 350 n/a Filter  28b 9.8 Centrifuge 1.9 45 0.75hrs (i.e 4 n/a n/a after addition of reactants complete)  28b 9.8Centrifuge 1.9 79 4 4 n/a n/a 29 10.3 Centrifuge n/a n/a n/a n/a 30 9.8Neutsch 1.9 0.5 n/a n/a 31 10.3 Neutsch 2.0 0.5 n/a n/a 32 9.8 Belt 2.00.5 n/a n/a 33 9.6 Tangential 1.9 81 2 2 n/a  7 flow filtration 34 10.1Tangential 1.9 69 4 4 n/a 22 flow filtration 35 10.3 Tangential 2.1 60 44 n/a 20 flow filtration 36 9.8 Wet 1.9 60 28 28 n/a Milled + Tangentialflow filtration 37 10.3 Wet 2.0 47 33 33 n/a Milled + Tangential flowfiltration(iv) Selection of a preferred filtration method and its operation.

In general, a filtration method is used to isolate the product fromslurry form, wash to a predetermined impurity end point and de-water thecake in order to obtain a material of sufficiently high solids contentto facilitate handling and for efficient drying. In the case oflaboratory filtration equipment de-watering is typically not carried outdue to the limitations of the equipment used and due to small quantitieshandled.

Tangential Flow Filtration (TFF)

A method whereby filtration rate increases when psd is less than 70microns is the Tangential Flow Filtration (diafiltration) method (Table4 and 5); however, diafiltration in general has significantly lowerfiltration rates (at all psd ranges) and is only suitable for filtrationof diluted slurries of more than 94 wt % moisture content Reactionslurry could be washed, but not concentrated, since moisture contentsbelow approximately 94 wt %, would lead to blockage of the TFF. Thewashed slurry would then require much greater energy input duringdrying. Consequently, separation by diafiltration is less preferred.

Neutsche Filter

Isolation and washing of the drug substance was also carried out using aNeutsche filter at a 7 kg production scale. This equipment gave goodproduct separation and washing but the specific filtration rate (kgproduct/m² h) was extremely slow and the filter cake contained up to 85wt % moisture content requiring much increased energy usage duringdrying. A cake depth of ˜7 cm was achieved in the Neutsche filter and 10cm in a filter/drier, whereas cake depths of 30 cm or more are notuncommon for filter/driers in other applications. Separation, by Neutschfilter we found to be less preferred for manufacture on a commercialscale because of lower filtration rate and limitations in handlinglarger amounts of the clay-like product.

Belt Filter

A belt filter is preferred as we found that these could be operated witha cake depth range of 15-25 mm at relatively high filtration rates. Thisfiltration method provides high filtration rates when psd is maintainedabove 70 microns.

Centrifuge

Different filtration methods were tested but best results were obtainedwith a filtration method using centrifuge which combines filtrationfollowed by washing and de-watering in one step. Centrifugal filtrationis preferred and provides advantages of high filtration rate andpreferred filter cake moisture content whilst maintaining the quality ofthe product (Table 4 and 5).

TABLE 5 Selection of filtration methods Preferred Moisture Slurry PSDContent of Preferred d50 at end of Wet Cake Precipitation hold timeExample Filtration Method 12 pH Method 9 Number Method % Range microns 28b Centrifuge 76-78 9.5-10 >70 34 or 35 Tangential Flow 92-95  10-10.5<70 Filtration 25 Lab Filter 85 9.5-10 >70 30 Neutsch 85 9.5-10 >70 32Belt 75-85 9.5-10 >70 Filter dryer 85 9.5-10 >70

Drying

We found that too much processing and handling; for example, such asoverdrying can present changes (such as growth of crystallite size) thatare unacceptable in the final mixed metal Mg:Fe compound How the APImorphology (vi) affects storage stability and downstream processing isshown in Table 6. How to control drying to achieve the required porosity(vii) and crystallite size (viii) is described in more detail in Table 7and 8.

(vi) Morphology

High daily, repeated long-term (chronic) dosages and restricted fluidintake are required for kidney patients. Consequently, a high dosage ofdrug substance is required in the final product (i.e. tablet) and themanufacture and qualities of the final product is therefore sensitive tothe form and shape (morphology) properties of the mixed metal compoundsdrug substance, unlike more typical formulations. This means that theproperties of the tablet, including key physical properties, and thetablet manufacturing processes, such as granulation, are often primarilyinfluenced by the properties of the mixed metal compound activesubstance rather than those of the excipients, as is more typically thecase. In order to be able to manufacture a pharmaceutical productcomprising such significant quantities of mixed metal compound with thecontrol and consistency necessary for pharmaceutical use, a means ofcontrolling an array of these physical properties of the mixed metalcompounds is essential

It is important to dry the material carefully as it is easy to changethe surface area or internal pore volume and hence change thetherapeutic activity (Table 6),

TABLE 6 Effect of API morphology on granules and tablets propertiesProperties API Granulation Tablet Change End Point Change AverageSurface Pore Pore phosphate Total water phosphate crystal Area volumevolume Phosphate binding added/kg Tablet Phosphate binding size N₂ N₂Water binding after API in Volume binding after Method 2 Method MethodMethod Method 3 storage dry mix Method Method 3 storage Example Angstrom14 14 15 mmol/g (12 mnths) Method 16 17 mmol/g (12 months) Number (Å)m²/g cm³/g cm³/g API % dm³ mm³ API % 38 151 54 0.17 0.36 0.68 −3 0.57470 0.67 −2 39 160 57 0.20 0.44 0.63 −5 0.60 477 0.63 −5 40 102 77 0.260.86 0.69 0.95 532 0.68 −2 41 97 74 0.31 1.10 0.68 N/A N/A N/A N/A 66 77119 0.30 0.68 0.79 −12.5

Table 6 shows how pore volume and surface area affects the control ofphosphate binding capacity, storage stability, the granulation processand the production of tablets. As a general rule, hydrotalcite typematerials of a higher surface area may be expected to have a higher ionexchange capacity and thereby higher phosphate binding; this can be seenfrom Example 66 which has a high surface area of 119 m²/g and also ahigh phosphate binding value. However, the material with the highersurface area of 119 m²/g was found to be less stable upon storagebecause phosphate binding activity decreased by 12%, We have found thata lower surface area range of between 40 and 80 m²/g is more preferredas it has the advantage of maintaining good phosphate binding (more than0.6 mmol/g API) that is importantly also essentially unchanged (only 5%or less change) upon storage over periods of up to years, making it moreviable as a an active pharmaceutical material. It may be expectedtypically that significantly higher surface areas would be required toattain such stable phosphate binding—such materials of lower surfaceareas (by N₂) of between 40-80 m²/g and have a pore volume (by N₂) of0.10-0.28 cm³/g and/or a pore volume (by water) of 0.3-0.6 cm³/g may beexpected to have greater sensitivity to any changes in the internalstructure resulting in the inhibition of access of the phosphate ionsinto the material and consequential reduction in phosphate bindingcapacity. Surprisingly, the data presented in Table 6 shows that allthese examples of mixed metal compound of lower surface areas arestorage stable and maintain good phosphate binding. Furthermore, thematerials of lower surface areas, in the range of between 40-70 m²/g andlow pore volume (water) of 0.3-0.6 cm³/g offers the advantage of adenser material that can then be processed into a dosage form that issmaller (i.e. as can be seen from Table 6 tablet volume of less than 500mm³) thereby improving tablet pill burden; a prevalent issue within thetreatment of renal patients Furthermore an additional surprising benefitis that such materials also exhibit no significant reduction in theuptake rate of phosphate, despite the lower surface areas. This facetcan be important when considering such materials for pharmaceuticalapplications in which the binding of phosphate needs to be rapid, suchas renal care. We have also found that the material of crystallite sizeless 200 Å binds greater than 80% of phosphate within 10 minutes(according to Test method 3 but measured at different time intervals)when maintained at a average particle size less than 100 μm, preferablyless than 50 μm, most preferred less than 10 μm and a surface area morethan 40 m²/g.

(vii) Manufacture of unaged, porous mixed metal compounds (drying)

We have found that the surface area of the drug substance is determinedby a combination of rate of drying, residence time, product rate perunit area and delta T (Table 7). The rate of drying is affected by boththe mode of drying and other process parameters, such as the producttemperature, heating surface/gas temperature.

A product of crystallite size between 90 and 200 Å and a surface area(by N₂) of between 40-80 m²/g, and/or pore volume (by N₂) of between0.10-0.28 cm³/g, and/or pore volume (by water) of between 0.3-0.6 cm³/gcan be achieved by exposing the crude product to a product temperatureof more than 80 but no greater than 150° C. and provide a rate of drying(water evaporation rate) of between 0.05 to 0.5 kg water per hour per kgof dry product and/or provide a dryer residence time of between 10minutes to 30 hours and/or a product rate per unit area of between 0-7kg product/(m²·hr) typically achieved by use of a high residence timedryer under a vacuum of pressure of 400 mbar (absolute) or less. Aproduct of low pore volume (by water) range of 0.3-0.6 cm³/g can beobtained by a combination of the centrifuge and use of agitatedspherical dryer method.

Alternatively, a product of crystallite size less than 140 Å and asurface area (by N₂) of between 80-150 m²/g, and/or pore volume (by N₂)of between 0.28-1.0 cm³/g, and/or pore volume (by water) of between0.6-1.2 cm³/g can be achieved by exposing the crude product to a producttemperature of more than 35° C. but no greater than 150° C. and providea rate of drying (water evaporation rate) of between 500 to 50000 kgwater per hour per kg of dry product and/or provide a dryer residencetime of less than 10 minutes and/or a delta T of between 0.2 to 1.0typically achieved by use of a short residence time dryer

TABLE 7 Effect of rate of drying on morphology Rate of Moisture DryingDryer Product rate Content Pore Pore Method 18 Residence per unit areaDried Surface Volume Volume Tap Bulk kg water/(kg Time Method 20 delta TProduct Area N₂ N₂ Water Density Flowability Example dried Method 19 kgproduct/ Method 21 Method 12 Method 14 Method 14 Method 15 Method 22Carr Index Number product · hr) hours (m² · hr) (Tin − Tout)/Tin wt %m²/g cm³/g cm³/g g/cm3 Method 23 42 0.09 29 2.1 n/a 19 0.50 0.50 43 0.1322 1.0 n/a 10 56 0.15 0.40 0.60 44 0.23 16 1.3 n/a 61 0.19 0.50 0.54 450.24 12 1.3 n/a 54 0.19 0.52 0.47 28 0.26 12 1.6 n/a 57 0.17 0.49 0.5132 46 0.28 11 2.1 n/a 54 0.18 0.48 0.56 47 0.31 9.9 2.0 n/a 61 0.17 0.520.52 31 15 0.2 n/a 8 71 0.28 30 40 0.21 18 0.2 n/a 77 0.26 1.10 0.36 4838000 0.0001 n/a 0.40 4 81 0.28 0.64 0.43 19 49 38000 0.0001 n/a 0.66 392 0.39 0.72 0.33 13 50 990 0.02 n/a 0.69 7 93 0.41 0.76 0.48 ND 51 9900.02 n/a 0.74 15 97 0.47 0.72 0.55 ND 52 990 0.02 n/a 0.76 7 119 0.560.74 0.50 22 66 38000 0.0001 n/a 119 0.68 38 0.27 12.9 1.4 n/a 7 53 0.1539 0.38 8.9 1.2 n/a 5 60 0.21 60 0.33 9.8 1.6 n/a 56 0.17 61 0.28 10.31.5 n/a 50 0.13 41 0.27 15.5 0.2 n/a 5(viii) Effect Of Rate Of Drying On Crystallite Size

Table 8 shows that the drying must be sufficiently rapid so as minimisecrystal growth, however bulk product temperatures exceeding 150° C. mustbe avoided in order to prevent damage to the characteristic materialstructure. Factors such as agitation during drying in long residencetime dryers were also found to effect crystallite size. For example,dried samples (such as obtained by Neutsche/Tray Oven) whereby nocontinuous agitation is applied tend to show smaller crystallite sizethan those obtained by a spherical drier. Therefore an optimum dryingregime exists.

TABLE 8 Effect of drying conditions on control of crystallite sizeProduct temperature Rate of Dryer in the Average Drying Residence deltaT dryer crystal Phosphate Method 18 Time Method Max size Binding kgwater/ Method 21 temperature Method 2 Method 3 Example Slurry SeparationDryer (kg dried 19 (T_(in) − achieved Angstrom mmol/g Number TreatmentMethod Method product · hr) hours T_(out))/T_(in) ° c. (Å) API 7 agedBuchner Tray Oven n/a 258 0.45 (lab) 42 unaged Centrifuge Agitated -0.09 29 n/a 90 195 0.63 Spherical 44 unaged Centrifuge Agitated - 0.2316 n/a 83 175 0.63 Spherical 45 unaged Centrifuge Agitated - 0.24 12 n/a74 160 0.67 Spherical 38 unaged Centrifuge Agitated - 0.27 12.9 n/a 85160 Spherical 39 unaged Centrifuge Agitated - 0.38 8.9 n/a 73 160Spherical 43 unaged Centrifuge Agitated - 0.13 22 n/a 75 157 0.66Spherical 60 unaged Centrifuge Agitated - 0.33 9.8 n/a 76 154 0.69Spherical 28 unaged Centrifuge Agitated - 0.26 12 n/a 72 151 0.67Spherical 49 Unaged Centrifuge Spin Flash 38000 0.0001 0.66 135 0.64 46unaged Centrifuge Agitated - 0.28 11 n/a 73 133 0.69 Spherical 47 unagedCentrifuge Agitated - 0.31 9.9 n/a 65 123 0.69 Spherical 51 unagedCentrifuge Spray 990 0.02 0.74 123 0.68 Dryer 52 unaged Centrifuge Spray990 0.02 0.76 117 0.70 Dryer 61 unaged Centrifuge Agitated - 0.28 10.3n/a 64 109 0.73 Spherical 40 Unaged Neutsch Tray Oven 0.21 18 n/a 1020.69 50 unaged TFF Spray 990 0.02 0.69 100 0.75 Dryer 41 unaged NeutschTray Oven 0.27 15.5 n/a 97 31 unaged Neutsch Tray Oven 15 n/a 94 0.66 48unaged Centrifuge Spin Flash 38000 0.0001 0.40 93 0.68 66 unaged TFFSpin Flash 38000 0.0001 0.48 77 0.79 2 unaged Buchner Tray Oven n/a n/an/a 69 0.73 (lab)

For those compounds wherein the average crystal size of the mixed metalcompound is from 10 to 20 nm (100 to 200 Å) preferably from 12 to 20 nm,the surface area (by N₂) is between 40-80 m²/g, pore volume (by N₂) isbetween 0.10-0.28 cm³/g and the pore volume (water) is from 0.3-0.6cm³/g. The compounds of average crystal size between 100 to 200 Å arepreferably obtained by use of a long residence agitated drying processsuch as an agitated spherical dryer wherein the rate of drying isbetween 0.09 to 0.31 kg water/(kg dried product·hr), more preferably arate of drying between 0.24 to 0.31 kg water/(kg dried product·hr)and/or a Product rate per unit area (kg product/m²·hr) of between 1-10more preferably between 2-7.

We have found, surprisingly that the advantages of the lower surfacearea product of crystallite size between 100 and 200 Å and/or lowsurface area 40-80 m²/g and/or low pore volume (water) 0.3-0.6 cm³/gprepared by a long residence drying process are good phosphate binding,storage stability and a denser material that can be processed into adosage form that is smaller thereby improving tablet pill burden.Average crystal size of less than 200 Å has the advantage of good,controlled phosphate binding. A average crystal size of between 120-200Å is preferred if product is dried to a moisture content less than 15 wt% (preferably between 5-10 wt %) of a batch size of between 50 and 1000kg when dried by a process of long residence drying with a agitatedspherical dryer and when preparing materials of a low surface area ofbetween 40 and 80 m² per gram and/or pore volume (water) of 0.3-0.6cm³/g. The low porosity product is preferably prepared from batch sizesbetween 50 and 1000 kg with a dryer residence time of between 3-30hours, more preferably between 5 to 30 hours and most preferred between9 to 30 hours

Milling

Optionally, after the drying step the dry material may be firstclassified to remove oversize particles by milling and/or sieving

(ix) Effects of PSD on Phosphate Binding and Magnesium Release

We have found that Mg release remains constant whereas phosphate bindingchanges as a function of particle size (Table 9). This is a surprisingresult as a smaller particle size distribution could be expected to havea larger surface area and therefore more susceptible to Mg release.However, the magnesium release does not appear to be significantlyaffected by changes in surface area when maintained at less than 80 m²/gdespite being milled to a particle size distribution (psd) with a (d50)of less than 60 micron when using this route. The constant Mg releaseenables a wider selection of a preferred psd range to improve phosphatebinding without compromising Mg release. The data from Table 9 showsthat a preferred particle size d50 is less than 177 micron, morepreferably less than 114, most preferred less than 60 micron.

TABLE 9 Effect of particle size distribution of dried product onphosphate binding and magnesium release (x) Effect of crystallite sizeon milling rate. PSD Phosphate Binding Mg Release Example Method 24Method 3 Method 3 Number d50 (microns) mmol/g API mmol/g API 53 487 0.390.17 54 315 0.52 0.18 55 177 0.63 0.17 56 114 0.64 0.17 57 60 0.67 0.1958 9 0.68 0.19 59 4 0.67 0.18

If processed incorrectly mixed metal compounds can become unacceptablyhard. This can lead to consequent issues of decreased milling rates andhigher energy input to achieve a preferred particle size. Theconsequence of this is that in achieving a given particle size it isessential that the crystallite size is not too low,

Table 10 shows that if the crystallite size is too low (i.e. of 120 Å orless) the milling rate will be reduced by more than 50% when compared tothat of crystallite size of 195 Å which will present difficulties atscale when milling to a particle size distribution with a d50 of lessthan 114 micron. For example, problems with occurrence ofnon-hydrotalcite phases such as MgO periclase, reduced milling rate ordecomposition of the product because of over-heating of the product canoccur. For those mixed metal compounds wherein the crystallite size isless than 120 Å it is preferred to use the short residence drying routewhich does not require milling.

TABLE 10 Effect of crystallite size on milling rate and phosphatebinding Milling Rate Crystallite Quantity of feed Phosphate Mg Sizeprocessed in a Binding Release Example Method 2 given time Method 3Method 3 Number Angstroms g/30 s mmol/g API mmol/g API 42 195 650 0.630.18 44 175 450 0.63 0.17 45 160 430 0.67 0.15 60 154 370 0.69 0.15 47123 300 0.69 0.15 61 110 280 0.73 0.14

If the reaction pH rises above pH 11 (and to a certain extent above pH10) we have found that the resultant mixed metal compounds is a muchharder material. It is therefore possible to prepare a softer materialby precipitation at pH 9.8 than at higher pH values. Consequently, notonly does precipitating at a pH of 9.8 provide the advantage ofincreased filterability we have also shown this to be of benefit forachieving increased milling rates.

Control of material hardness is also important because this may alsoincrease the potential for pickup of low levels of trace-metals from themilling equipment. When the material is harder it also has to be milledharder which in turn can lead to higher temperatures being generatedduring milling which provide a milled material which can containdecomposition products or may be too dry (less than 5 wt % moisturecontent as determined by LOD) which in turn can lead to problems withhandling and the downstream processing.

(xi) Methods of Micronisation

If the moisture content of the unmilled product is above 10 wt % thenthe product can become too sticky for milling whereas if less than 5 wt% the product after milling will be too dry and would then be lessstable upon storage and/or provide problems in processing into tabletformulations. We found that the milling process results in a further 2wt % loss of moisture resulting in a milled product. We thereforetypically target a moisture content of between 7 and 10 wt % for theunmilled material

The chemical (i.e. molar ratio of Mg:Fe of 2.1) and physical properties(i.e. surface area and particle size) of the mixed metal compoundscomposition favour equilibration to a 5-8 wt % moisture content and assuch may be less stable upon storage (i.e. have a tendency tore-hydrate) if manufactured to a moisture content less than 5 wt %.

We have found that this compound can be manufactured using a processcomprising a short residence drying step such that the resultantrepresentative material has both small average crystal size and highsurface area but also importantly and surprisingly exhibits highphosphate binding even when the material is not milled further. Therequirement for no milling has the advantage of reduced processingsteps. A further advantage is that such material can be suitable fortabletting processes without the need for wet granulation due to theadvantageous flow properties. Therefore, in one aspect the presentinvention provides a mixed metal compound wherein the average crystalsize of the mixed metal compound is less than 20 nm (200 Å); in thisaspect preferably the surface area is from 80 to 145 m² per gram. Thedata from Table 11 shows that for a mixed metal compound with a surfacearea from 80 to 145 m² per gram the preferred particle size d50 is lessthan 343 micron, more preferably less than 296, even more preferablyless than 203, most preferred less than 31 micron.

TABLE 11 Micronisation required PSD Phosphate Mg Surface to achieve goodMethod 24 Binding Release Area N₂ phosphate binding Example d50 Method 3Method 3 Method 14 (>0.6 mmol/g) Number Micronised (microns) mmol/g APImmol/g API m²/g yes/no 59 no 343 0.51 0.21 67 yes 59 yes 4 0.67 0.18 52n/a 48 no 296 0.64 0.14 81 no 49 no 203 0.68 0.15 92 no 51 no 31 0.680.11 97 no 52 no 27 0.7 0.11 119 no 50 no 20 0.75 0.10 93 no

The compound of higher surface area of 80-145 m² can be manufacturedusing a process comprising a short residence drying step such that theresultant representative material has both small average crystal sizeand high surface area but also importantly and surprisingly exhibitshigh phosphate binding even when the material is not milled further. Therequirement for no milling has the advantage of reduced processing stepsand avoids any hardness issues. A further advantage is that suchmaterial can be suitable for tabletting processes without the need forwet granulation.

Impurity

Mixed metal compounds may be synthesised by various techniques; however,it is difficult to control impurity levels of compounds when isolated inthe unaged form, to a pharmaceutical grade and when prepared Al-freeespecially when considering that mixed metal compounds are prepared fromminerals containing significant levels of trace-metal impurities some ofwhich may be in the form of heavy metals. In particular, compoundsprepared from iron minerals are considerably intermeshed with othermetal types as these ultimately are derived from minerals that exist innature. Some of these metals may compete with the magnesium and iron forformation of the mixed metal compound and get locked into thehydrotalcite phase instead of forming more soluble salts which arereadily washed out during the washing process. There is therefore a needto control trace metal impurity levels by selecting preferred conditionsand recipe during the precipitation stage; this in order to meetregulatory guidelines whilst obtained via a manufacturing process thatcan deliver this at scale.

Other impurities, such as sodium and sulphate must be controlled inorder that the drug substance is of acceptable quality for humanconsumption. The sodium concentration is controlled through washing ofthe isolated drug substance cake.

During the filtration and washing step of the manufacturing process, theslurry is formed into a cake (with the removal of excess mother liquor).The resultant cake is then washed with water to remove excess sodium,sulphate and carbonate down to levels acceptable for the final use ofthe material.

For pharmaceutical use it is important to be able to identify andcontrol the crystal phase of interest. The way the material is processedinfluences this, when preparing a compound from 2 different metal typesit is possible that it may precipitate as a mixture of single metalcompounds instead of a mixed metal compound. Mixed metal compounds aremanufactured by co-precipitation which can encourage the formation ofdifferent crystalline phases in addition to the hydrotalcite phase.There is therefore the need for a Al-free mixed metal compounds whichare also free of any other crystalline phases as determined by theabsence of XRD diffraction lines except those attributed to thehydrotalcite phase When prepared according to the process defined forthe unaged samples of crystallite size less than 200 Å we have foundthat the hydrotalcite phase has the following diffraction X-raydiffraction analysis without the presence of any other crystallinephases: dA (‘d’ spacings) 7.74, 3.86, 2.62, 2.33, 1.97, 1.55, 1.52,1.44. Five additional peaks at dA 3.20, 1.76, 1.64, 1.48, 1.40 are onlyresolved in more crystalline samples i.e. of crystallite size above 200Å, typically as a result of ageing

Trace metal impurities must be controlled in order that the drugsubstance is of acceptable quality for human consumption. We foundsurprisingly that trace metal concentrations can be controlled by thereaction pH, reaction hold time (ageing) and not only as would beexpected by the selection of raw materials of appropriate quality orwashing. For example, Table 12 shows how we have been able to furtherreduce the aluminium (Al) and lead (Pb) levels by control of pH, controlof sodium carbonate excess and control of ageing.

TABLE 12 Effect of recipe, reaction conditions on trace metals contentmixed metal compound Excess Total Moles Heavy Precipitation Na2CO3 Al CrPb Metals Na₂O Example Trivalent Slurry pH in Recipe Method 25 Method 25Method 25 Method 26 Method 1 Number Metal Source Treatment pH Moles ppmppm ppm ppm wt % 62 Al source unaged 9.8 2.7 96160 n/d n/d n/d <0.5 63Fe source unaged 10.5 4.0 52 32 7 <15 <0.5 (A) 64 Fe source unaged 10.52.7 56 34 3 <11 <0.5 (A)  9b Fe source unaged 9.8 2.7 58 34 <1 <9 <0.5(A) 23 Fe source aged 9.8 4.0 78 33 <1 <10 <0.5 (A) 17 Fe source unaged9.8 2.7 <30 1 <1 <8 <0.5 (B) 28 Fe source unaged 9.8 2.7 <30 2 <1 <9<0.5 (B)  9 Fe source aged 9.8 2.7 57 1 <1 <9 <0.5 (B)

From Table 12 it is possible to conclude that even when changing from asolution (Å) of GPR grade Rectapur to a more pure ferric source (B) suchas a solution (40.4 to 42.9 wt % ferric sulphate of water industrystandard suitable for human consumption conforms to BS EN 890:2004), thealuminium levels may be decreased further (i.e. to less than 30 ppm) byavoiding excessive ageing (i.e. wherein the crystallite size is >200 Å)

Example 62 was prepared with solid aluminium sulphate of Alfa Aesar 98%CAS 17927-65-0 instead of ferric sulphate. All other raw materials wereof the same source.

All samples shown in Table 12 were washed equally as indicated by low(<0.5 wt %) and similar Na₂O levels. The washing process was developedsuch as to provide the required Na₂O levels.

As discussed herein the aluminium levels of the mixed metal compound areless than 10000 ppm. This level is considered suitable Al exposure for ahealthy individual and is typical of pharmaceutical grade compounds(i.e. of 99% purity). In contrast, mixed metal compounds commerciallyavailable as antacids in the form of a Mg:Al mole ratio of 3:1,typically contain ten times as much Al (i.e. up to 100000 ppm aluminium)and are therefore not suitable for long term use. Renal patients areprone to aluminium accumulation it is therefore more preferred if thealuminium content is less than 2000 ppm (>99.8% purity) based on a totaldaily intake of 6 g/day and general regulatory guidance

We have found that a Al level of 1000 ppm (99.9% purity) is achievablewhen using a large scale process for manufacture of unaged materials.For renal patients an aluminium content as low as possible is preferredand therefore a aluminium content of less than 1000 ppm is morepreferable. Using our process we can typically achieve aluminum levelsless than 100 ppm; therefore aluminium levels less than 100 ppm are evenmore preferred. By careful control of reaction conditions we can achievealuminium levels less than 30 ppm which is most preferred

The data of Table 12 also demonstrates that it is possible to maintainlead (Pb) levels below the detection limit of <1 ppm when precipitatedat pH 9.8 and using an excess of 2.7 moles Na₂CO₃ in the recipe insteadof precipitating the mixed metal compound at pH 10.5 and using an excessof 4.0 moles Na₂CO₃ even when using a more impure source of ferricsulphate. We also found that the total heavy metal content could bemaintained at less than 10 ppm total heavy metals (Test Method 26) whenusing the preferred recipe of pH 9.8 and an excess of 27 moles Na₂CO₃.

Chromium (Cr) levels are required to be limited to <25 ppm according tothe guideline of metal reagents for medicinal compoundsCHMP/CWP/QWP/4446/00 Table 12 demonstrates that we have been able tolower the chromium levels from approximately 35 ppm to below thedetection limit (less than 1 ppm).

All publications and patents and patent applications mentioned in theabove specification are herein incorporated by reference, Variousmodifications and variations of the present invention will be apparentto those skilled in the art without departing from the scope and spiritof the invention. Although the invention has been described inconnection with specific preferred embodiments, it should be understoodthat the invention as claimed should not be unduly limited to suchspecific embodiments. Indeed, various modifications of the describedmodes for carrying out the invention which are obvious to those skilledin chemistry, biology or related fields are intended to be within thescope of the following claims.

1. A method of producing a mixed metal compound comprising at least Mg²⁺and at least Fe³⁺ having an aluminium content of less than 10000 ppm,having an average crystal size of less than 20 nm (200 Å) comprising thesteps of: (a) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ and NaOHto produce a slurry, wherein the pH of the slurry is maintained at from9.5 to 11, and wherein the Na₂CO₃ is provided at an excess of 0 to 4.0moles than is required to complete the reaction (b) subjecting theslurry to mixing under conditions providing a power per unit volume of0.03 to 1.6 kW/m³ (c) separating the mixed metal compound from theslurry, to obtain a crude product having a dry solid content of at least10 wt % (d) drying the crude product either by (i) heating the crudeproduct to a temperature of no greater than 150° C. and sufficient toprovide a water evaporation rate of 0.05 to 1.5 kg water per hour per kgof dry product, or (ii) exposing the crude product to rapid drying at awater evaporation rate of 500 to 50000 kg water per hour per kg of dryproduct.
 2. A method according to claim 1 wherein the compound is of theformulaM^(II) _(1-x)M^(III) _(x)(OH)₂A^(n−) _(y) .mH₂O  (II) wherein M^(II) isone or more bivalent metals and is at least Mg²⁺; M^(III) is one or moretrivalent metals and is at least Fe³⁺; A^(n−) is one or more n-valentanions and is at least CO₃ ²⁻; x/Σyn is from 1 to 1.2 0<x≦0.4, 0<y≦1 and0<m≦10.
 3. A method according to claim 2 wherein x/Σyn is from 1.05 to1.15
 4. A method according to claim 2 wherein x/Σyn is
 1. 5. A methodaccording to claim 1 wherein the molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to1.5:1.
 6. A method according to claim 1 wherein the compound has anaverage crystal size of from 10 to 20 nm (100 to 200 Å).
 7. A methodaccording to claim 1 wherein the compound has an aluminium content ofless than 100 ppm.
 8. (canceled)
 9. (canceled)
 10. A method according toclaim 1 wherein the interlayer sulphate content of the compound is from1.8 to 5 wt %.
 11. (canceled)
 12. (canceled)
 13. (canceled) 14.(canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. A methodaccording to claim 1 wherein the Na₂CO₃ is provided at an excess of 2.0to 4.0 moles than required to complete the reaction.
 19. A methodaccording to claim 1 wherein step (a) comprises: (A) combining a Mg²⁺salt and a Fe³⁺ salt with Na₂CO₃ and NaOH to produce a slurry, whereinthe slurry is maintained to a temperature between 15 and 30° C., and:(i) wherein the pH of the slurry is maintained at from 9.5 to less than9.8, and wherein the Na₂CO₃ is provided at an excess of greater than 1.0to no greater than 5.0 moles than is required to complete the reaction;or (ii) wherein the pH of the slurry is maintained at from 9.5 to lessthan 10, and wherein the Na₂CO₃ is provided at an excess of greater than1.0 to no greater than 4.0 moles than is required to complete thereaction; or (iii) wherein the pH of the slurry is maintained at from9.5 to no greater than 10.1, and wherein the Na₂CO₃ is provided at anexcess of greater than 1.0 to no greater than 2.7 moles than is requiredto complete the reaction; or (iv) wherein the pH of the slurry ismaintained at from 9.5 to 10.5, and wherein the Na₂CO₃ is provided at anexcess of from greater than 1.0 to no greater than 2.0 moles than isrequired to complete the reaction; or (v) wherein the pH of the slurryis maintained at from greater than 9.5 to no greater than 11, andwherein the Na₂CO₃ is provided at an excess of from 0.0 to no greaterthan 1.0 moles than is required to complete the reaction; or step (a)comprises: (B) combining a Mg²⁺ salt and a Fe³⁺ salt with Na₂CO₃ andNaOH to produce a slurry, wherein the slurry is maintained to atemperature from 30 to 60° C., and: (i) wherein the pH of the slurry ismaintained at from greater than 9.5 to less than 11, and wherein theNa₂CO₃ is provided at an excess of greater than 0 to less than 2 molesthan is required to complete the reaction; or (ii) wherein the pH of theslurry is maintained at from greater than 9.5 to less than 10.5, andwherein the Na₂CO₃ is provided at an excess of greater than 0 to lessthan 2.7 moles than is required to complete the reaction; or (iii)wherein the pH of the slurry is maintained at from greater than 9.5 toless than 10, and wherein the Na₂CO₃ is provided at an excess of greaterthan 0 to less than 4 moles than is required to complete the reaction.20. A method according to claim 1 wherein in step (b) the slurry issubjected to mixing under conditions providing a power per unit volumeof 0.03 to 1.6 kW/m³ while maintaining a slurry temperature of less than65° C.
 21. A method according to claim 1 wherein in step (b) the slurryconditions are controlled such that a d50 particle size distribution ofat least 40 μm is provided.
 22. A method according to claim 1 wherein instep (c) the mixed metal compound is separated from the slurry, toobtain a crude product having a dry solid content of at least 15 wt %.23. (canceled)
 24. A method according to claim 1 wherein in step (d) thecrude product is dried by (i) heating the crude product to a temperatureof no greater than 150° C. and sufficient to provide a water evaporationrate of 0.05 to 1.5 kg water per hour per kg of dry product. 25.(canceled)
 26. A method according to claim 1 wherein in step (d) thecrude product is dried by exposing the crude product to rapid drying ata water evaporation rate of 500 to 50000 kg water per hour per kg of dryproduct.
 27. (canceled)
 28. (canceled)
 29. A method according to claim 1wherein the crude product is washed prior to step (d).
 30. (canceled)31. (canceled)
 32. A method according to claim 31 wherein the driedcrude product is milled to a d50 average particle size of less than 200μm.
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. A method accordingto claim 31 wherein the milled dried crude product has a water contentof 1 to 10 wt % based on the total weight of the dried crude product.37. (canceled)
 38. (canceled)
 39. (canceled)
 40. (canceled)
 41. A methodaccording to claim 1 for the production of a mixed metal compound havinga total heavy metal content of less than 15 ppm, a lead content lessthan 10 ppm, a chromium level less than 35 ppm and a sodium content(expressed as Na₂O) of less than 1 wt %.
 42. (canceled)
 43. (canceled)44. (canceled)
 45. A method of producing a mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺ having an aluminium contentof less than 10000 ppm, having an average crystal size of less than 20nm (200 Å); the method comprising the step of: (a) combining a Mg²⁺ saltand a Fe³⁺ salt with Na₂CO₃ and NaOH to produce a slurry, wherein theslurry is maintained to a temperature between 15 and 30° C., and: (i)wherein the pH of the slurry is maintained at from 9.5 to less than 9.8,and wherein the Na₂CO₃ is provided at an excess of greater than 1.0 tono greater than 5.0 moles than is required to complete the reaction; or(ii) wherein the pH of the slurry is maintained at from 9.5 to less than10, and wherein the Na₂CO₃ is provided at an excess of greater than 1.0to no greater than 4.0 moles than is required to complete the reaction;or (iii) wherein the pH of the slurry is maintained at from 9.5 to nogreater than 10.1, and wherein the Na₂CO₃ is provided at an excess ofgreater than 1.0 to no greater than 2.7 moles than is required tocomplete the reaction; or (iv) wherein the pH of the slurry ismaintained at from 9.5 to 10.5, and wherein the Na₂CO₃ is provided at anexcess of from greater than 1.0 to no greater than 2.0 moles than isrequired to complete the reaction; or (v) wherein the pH of the slurryis maintained at from greater than 9.5 to no greater than 11, andwherein the Na₂CO₃ is provided at an excess of from 0.0 to no greaterthan 1.0 moles than is required to complete the reaction; or the methodcomprising the step of: (b) combining a Mg²⁺ salt and a Fe³⁺ salt withNa₂CO₃ and NaOH to produce a slurry, wherein the slurry is maintained toa temperature from 30 to 60° C., and: (i) wherein the pH of the slurryis maintained at from greater than 9.5 to less than 11, and wherein theNa₂CO₃ is provided at an excess of greater than 0 to less than 2 molesthan is required to complete the reaction; or (ii) wherein the pH of theslurry is maintained at from greater than 9.5 to less than 10.5, andwherein the Na₂CO₃ is provided at an excess of greater than 0 to lessthan 2.7 moles than is required to complete the reaction; or (iii)wherein the pH of the slurry is maintained at from greater than 9.5 toless than 10, and wherein the Na₂CO₃ is provided at an excess of greaterthan 0 to less than 4 moles than is required to complete the reaction.46. (canceled)
 47. A mixed metal compound obtained or obtainable by themethod of claim
 1. 48. A mixed metal compound comprising at least Mg²⁺and at least Fe³⁺, wherein the molar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to1.5:1, the mixed metal compound has an aluminium content of less than10000 ppm, the average crystal size of the mixed metal compound is from10 to 20 nm (100 to 200 Å), and the d50 average particle size of themixed metal compound is less than 300 μm.
 49. (canceled)
 50. A mixedmetal compound comprising at least Mg²⁺ and at least Fe³⁺, wherein themolar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1, the mixed metal compoundhas an aluminium content of less than 10000 ppm, the average crystalsize of the mixed metal compound is from 10 to 20 nm (100 to 200 Å), andthe water pore volume of the mixed metal compound is from 0.25 to 0.7cm³/g of mixed metal compound.
 51. (canceled)
 52. (canceled)
 53. A mixedmetal compound comprising at least Mg²⁺ and at least Fe³⁺, wherein themolar ratio of Mg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1, the mixed metal compoundhas an aluminium content of less than 10000 ppm, and (a)(i) the averagecrystal size of the mixed metal compound is from 10 to 20 nm (100 to 200Å) and (a)(ii) the interlayer sulphate content of the compound is from 2to 5 wt %; or (b)(i) the average crystal size of the mixed metalcompound is less than 20 nm (200 Å) and (b)(ii) the interlayer sulphatecontent of the compound is from 2.1 to 5 wt %.
 54. (canceled) 55.(canceled)
 56. (canceled)
 57. (canceled)
 58. A mixed metal compoundcomprising at least Mg²⁺ and at least Fe³⁺, wherein the molar ratio ofMg²⁺ to Fe³⁺ is 2.5:1 to 1.5:1, the mixed metal compound has analuminium content of less than 10000 ppm, and (a)(i) the average crystalsize of the mixed metal compound is less than 20 nm (200 Å) and (a)(ii)the surface area is from 80 to 145 m² per gram of compound or (b)(i) theaverage crystal size of the mixed metal compound is from 10 to 20 nm(100 to 200 Å) and (b)(ii) the surface area is from 40 to 80 m² per gramof compound.
 59. (canceled)
 60. (canceled)
 61. (canceled)
 62. (canceled)63. A mixed metal compound according to claim 58 wherein the water porevolume of the mixed metal compound is from 0.25 to 0.7 cm³/g of mixedmetal compound.
 64. A compound according to claim 48 wherein thecompound is of the formulaM^(II) _(1-x)M^(III) x(OH)₂A^(n−) _(y) .mH₂O wherein M^(II) is one ormore bivalent metals and is at least Mg²⁺; M^(III) is one or moretrivalent metals and is at least Fe³⁺; A^(n−) is one or more n-valentanions and is at least CO₃ ²⁻; x/Σyn is from 1 to 1.2 0<x≦0.4, 0<y≦1 and0<m≦10.
 65. A compound according to claim 64 wherein x/Σyn is from 1.05to 1.15.
 66. A compound according to claim 64 wherein x/Σyn is
 1. 67. Acompound according to claim 48 wherein the compound has an aluminiumcontent of less than 100 ppm
 68. (canceled)
 69. A compound according toclaim 48 wherein the interlayer sulphate content of the compound is from2 to 5 wt %.
 70. A compound according to claim 48 wherein the compoundhas a d50 average particle size of less than 100 μm.
 71. (canceled) 72.(canceled)
 73. A compound according to claim 48 wherein the water porevolume of the mixed metal compound is from 0.25 to 0.7 cm³/g of mixedmetal compound.
 74. A compound according to claim 48 wherein thecompound has a dry solid content of at least 20 wt %
 75. A mixed metalcompound according to claim 47 for use as a medicament.
 76. A mixedmetal compound according to claim 47 for binding phosphate.
 77. A mixedmetal compound according to claim 47 for use in the treatment ofhyperphosphataemia.
 78. A pharmaceutical composition comprising a mixedmetal compound as defined in claim 47 and one or more pharmaceuticallyacceptable adjuvants, excipients, diluents or carriers.
 79. (canceled)80. (canceled)
 81. (canceled)
 82. (canceled)